vol 21 7 2017documents.irevues.inist.fr/bitstream/handle/2042/68273/vol_21_7_2017.pdf · in...

Volume 1 - Number 1 May - September 1997

Volume 21 - Number 7 July 2017

The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with

the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific

Research (CNRS) on its electronic publishing platform I-Revues.

Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.

Atlas of Genetics and Cytogenetics in Oncology and Haematology

INIST-CNRS OPEN ACCESS JOURNAL

Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access,

devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.

It is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology.

One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the

clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer

genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university

(university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using

information technology, between the increasing amount of knowledge and the individual, having to use the information.

Towards a personalized medicine of cancer.

It presents structured review articles ("cards") on:

1- Genes,

2- Leukemias,

3- Solid tumors,

4- Cancer-prone diseases, and also

5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics.

It also present

6- Case reports in hematology and

7- Educational items in the various related topics for students in Medicine and in Sciences.

The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.

See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf

Editorial correspondance

Jean-Loup Huret, MD, PhD,

Genetics, Department of Medical Information,

University Hospital

F-86021 Poitiers, France

phone +33 5 49 44 45 46

[email protected]

Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 12 times a year by ARMGHM, a non

profit organisation, and by the INstitute for Scientific and Technical Information of

the French National Center for Scientific Research (INIST-CNRS) since 2008.

The Atlas is hosted by INIST-CNRS (http://www.inist.fr)

Staff: Vanessa Le Berre

Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).

Publisher Contact: INIST-CNRS

Mailing Address: Catherine Morel, 2,Allée du Parc de Brabois, CS 10130, 54519 Vandoeuvre-lès-Nancy France.

Email Address:[email protected]

Articles of the ATLAS are free in PDF format, and metadata are available on the web in Dublin Core XML format and freely

harvestable.A Digital object identifier (DOI®), recorded at the International Agency CrossRefhttp://www.crossref.org/ is

assigned to each article.

http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262

http://international.inist.fr/

http://www.cnrs.fr/index.html

http://irevues.inist.fr/

http://international.inist.fr/

http://www.cnrs.fr/index.html

mailto:[email protected]

http://www.crossref.org/

http://www.atlasgeneticsoncology.org/

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7)

Atlas of Genetics and Cytogenetics

in Oncology and Haematology


Editor-in-Chief Jean-Loup Huret (Poitiers, France) Lymphomas Section Editor Antonino Carbone (Aviano, Italy)

Myeloid Malignancies Section Editor Robert S. Ohgami (Stanford, California)

Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands)

Head and Neck Tumors Section Editor Cécile Badoual (Paris, France)

Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts)

Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland)

Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy)

Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil)

DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands)

Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK)

Mitosis Section Editor Patrizia Lavia (Rome, Italy)

WNT pathway Section Editor Alessandro Beghini (Milano, Italy)

B-cell activation Section Editors Anette Gjörloff Wingren and Barnabas Nyesiga (Malmö,

Sweden)

Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France)

Board Members

Sreeparna

Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected]

Alessandro

Beghini Department of Health Sciences, University of Milan, Italy; [email protected]

Judith Bovée 2300 RC Leiden, The Netherlands; [email protected]

Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy;

[email protected]

Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected]

François

Desangles

IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212,

91223 Bretigny-sur-Orge, France; [email protected]

Enric Domingo Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK

[email protected]

Ayse Elif Erson-

Bensan Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected]

Ad Geurts van

Kessel

Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB

Nijmegen, The Netherlands; [email protected]

Oskar A. Haas Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer

Research Institute Vienna, Vienna, Austria. [email protected]

Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected]

Nyla Heerema Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA;

[email protected]

Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected]

Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico

Roderick Mc Leod Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures,

Braunschweig, Germany; [email protected]

Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected]

Fredrik Mertens Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden;

[email protected]

Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected]

Felix Mitelman Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden;

[email protected]

Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected]

Stefan Nagel Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures,

Braunschweig, Germany; [email protected]

Florence

Pedeutour

Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France;

[email protected]

Susana Raimondi Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee

38105-3678, USA; [email protected]

Clelia Tiziana

Storlazzi Department of Biology, University of Bari, Bari, Italy; [email protected]

Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected]

Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected]

Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected]

Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy;

[email protected]

Franck Viguié Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Universitaire Necker-Enfants

Malades, 75015 Paris, France; [email protected]




Volume 21, Number 7, July 2017

Table of contents

Gene Section

ATM (ataxia telangiectasia mutated) 237 Yossi Shiloh

Leukaemia Section

del (5q) solely in Myelodysplastic syndrome 249 Nahid Shahmarvand, Robert S. Ohgami

del(9p) in Acute Lymphoblastic Leukemia 252 Anwar N. Mohamed

der(X)t(X;8)(q28;q11.2) 256 Tatiana Gindina

t(1;9)(q24;q34) RCSD1/ABL1 259 Adriana Zamecnikova, Soad al Bahar

t(3;9)(p13;q34.1) FOXP1/ABL1 263 Julie Sanford Biggerstaff

t(1;22)(p36;q11) IGL/PRDM16 265 Jean-Loup Huret

t(1;3)(p36;q21) RPN1/PRDM16 267 Jean-Loup Huret

t(1;17)(p36;q21) WNT3 or NSF/PRDM16 270 Jean-Loup Huret

Cancer Prone Disease Section

Fanconi anemia 272 Filippo Rosselli

Gene Section Review

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 237



ATM (ataxia telangiectasia mutated) Yossi Shiloh

The David and Inez Myers Chair in Cancer Research, Department of Human Molecular Genetics and

Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; yossih+AEA-

post.tau.ac.il

Published in Atlas Database: October 2016

Online updated version : http://AtlasGeneticsOncology.org/Genes/ATMID123.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68260/10-2016-ATMID123.pdf DOI: 10.4267/2042/68260

This article is an update of : Uhrhammer N, Bay JO, Gatti RA. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol 2003;7(1) Uhrhammer N, Bay JO, Gatti RA. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol 1999;3(4) Huret JL. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol 1998;2(3)

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract

Review on ATM, with data on DNA, on the protein

encoded, and where the gene is implicated.

Keywords

Ataxia telangiectasia; Cerebellar ataxia;

Telangiectasia; Immunodeficiency; T- cell

malignancies; B-cell malignancies; Carcinomas;

Senescence; Chromosome instability syndrome;

DNA double-strand breaks; Translocation;

Oxidative stress; Homeostasis; ATM; chromosome.

Identity

HGNC (Hugo): ATM

Location: 11q22.3

Note

See also, in Deep Insight section: Ataxia-

Telangiectasia and variants.

DNA/RNA

ATM (11q22.3) in normal cells: PAC 1053F10 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

Description

The ATM gene extends over 184 kb and contains 66

exons producing a 13 kb mRNA (Uziel T et al.,

1996; Platzer M et al., 1997); numerous Alu and

Lime sequences.

Transcription

Alternative exons 1a and 1b; initiation codon lies

within exon 4; 12 kb transcript with a 9.2 kb of

coding sequence.

The ATM promotor is bi-directional and also directs

the transcription of the NPAT gene.

Protein

Description

ATM is a homeostatic protein kinase with an

extremely broad range of roles in various cellular

circuits (Shiloh Y et al., 2013; Guleria A et al., 2016;

Shiloh Y, 2014; Cremona CA et al., 2014; Ambrose

M et al., 2013; Espach Y et al., 2015; Awasthi P et

al., 2016). This large polypeptide of 350 kDa and

3,056 residues bears a PI3 kinase signature within its

carboxy-terminal catalytic site, but has the catalytic

activity of a serine-threonine protein kinase. This

motif is characteristic of a protein family of which

ATM is a member - the PI-3 kinase-like protein

kinases (PIKKs; Lovejoy CA et al., 2009;

Bareti+ACY-cacute; D et al., 2014).

ATM (ataxia telangiectasia mutated) Shiloh Y


This family also contains the MTOR protein, which

regulates many signaling pathways in response to

nutrient levels, growth factors and energy balance

(Alayev A et al., 2013; Cornu M et al., 2013); the

catalytic subunit of the DNA-dependent protein

kinase (DNA-PKcs), which is involved in the NHEJ

pathway of double strand breaks (DSB) repair and

other genotoxic stress responses (Davis AJ et al.,

2014; Jette N et al., 2015), SMG1, which plays a key

role in nonsense-mediated mRNA decay (Yamashita

A, 2013); and ATR, which responds to stalled

replication forks and a variety of DNA lesions that

lead to the formation of single-stranded DNA,

including deeply resected DSBs (Errico A et al.,

2012; Mar+ACY-eacute;chal A et al., 2013; Awasthi

P et al., 2016). The redundancy, crosstalk and

collaboration between the latter three PIKKs, which

collectively respond to a broad spectrum of

genotoxic stresses, are being extensively

investigated (Lovejoy CA et al., 2009; Mar+ACY-

eacute;chal A et al., 2013; Sirbu BM et al., 2013;

Thompson LH, 2012; Gobbini E et al., 2013; Chen

BP et al., 2012).

It should be noted that in A-T patients, the two

PIKKs that converse and cooperate with ATM in the

response to genotoxic stress, ATR and DNA-PK,

remain active. In view of the functional relationships

between the three protein kinases, some of ATM's

duties are probably carried out to a certain extent by

ATR and/or DNA-PK, in A-T cells. On the other

hand, the lack of a very versatile member of this trio

may lead to some suboptimal responses of the other

two, if they depend on the crosstalk with ATM. This

interesting question is a subject of intensive research.

Expression

ATM is expressed in all tissues.

Localisation Mostly in the nucleus throughout all stages of the cell

cycle.

Function Homeostatic protein kinase involved in many

cellular circuits. A primary role in the DNA damage

response. Activated vigorously by DNA double-

strand breaks and activates a broad network of

responses. ATM initiates cell cycle checkpoints in

response to double-strand DNA breaks by

phosphorylating TP53, BRCA1, H2AFX, ABL1,

NFKBIA and CHEK1, as well as other targets; in

certain types of tissues ATM inhibits radiation-

induced, TP53-dependent apoptosis.

Double strand breaks The most widely

documented function of ATM, and the one

associated with its most vigorous activation, is the

mobilization of the complex signaling network that

responds to DSBs in the DNA (Shiloh Y et al., 2013;

Cremona CA et al., 2014; Awasthi P et al., 2016;

Thompson LH, 2012; McKinnon PJ, 2012). DSBs

are induced by exogenous DNA breaking agents or

endogenous reactive oxygen species (Schieber M et

al., 2014), and are an integral part of physiological

processes including meiotic recombination (Borde V

et al., 2013; Lange J et al., 2011) and the

rearrangement of antigen receptor genes in the

adaptive immune system (Alt FW et al., 2013).

DSBs are repaired via nonhomologous end-joining

(NHEJ), or homologous recombination repair (HRR;

Shibata A et al., 2014; Chapman JR et al., 2012;

Jasin M et al., 2013; Radhakrishnan SK et al., 2014).

DSBs also activates the DDR, a vast signaling

network that mobilizes special cell cycle

checkpoints, extensively alters the cellular

transcriptome, and changes the turnover, activity and

function of numerous proteins that ultimately leads

to modulation of numerous cellular circuits. This

network is based on a core of dedicated DDR players

and the ad-hoc recruitment of proteins from many

other arenas of cellular metabolism, which typically

undergo special, damage-induced post-translational

modifications (PTMs; Shiloh Y et al., 2013; Sirbu

BM et al., 2013; Thompson LH, 2012) (Goodarzi

AA et al., 2013; Panier S et al., 2013; Polo SE et al.,

2011).

Once ATM mobilizes the vast DDR network in

response to a DSB (McKinnon PJ, 2012; Shiloh Y et

al., 2013; Bhatti S et al., 2011), its protein kinase

activity is rapidly enhanced, and PTMs on the ATM

molecule are induced, including several

autophosphorylations and an acetylation (Shiloh Y et

al., 2013; Bhatti S et al., 2011; Bakkenist CJ et al.,

2003; Kozlov SV et al., 2006; Bensimon A et al.,

2010; Sun Y et al., 2007; Kaidi A et al., 2013; Paull

TT, 2015).

ATM subsequently phosphorylates key players in

various arms of the DSB response network (Shiloh

Y et al., 2013; Bensimon A et al., 2010; Matsuoka S

et al., 2007; Mu JJ et al., 2007; Bensimon A et al.,

2011), including other protein kinases that in turn

phosphorylate still other targets (Bensimon A et al.,

2011).

Single-strand break repair and base excision

repair A broader, overarching role for ATM in

maintaining genome stability was recently suggested

in addition to mobilizing the DSB response (Shiloh

Y, 2014). According to this conjecture, ATM

supports other DNA repair pathways that respond to

various genotoxic stresses, among them single-

strand break repair (SSBR; Khoronenkova SV et al.,

2015) and base excision repair (BER) - a cardinal

pathway in dealing with the daily nuclear and

mitochondrial DNA damage caused by endogenous

agents (Wallace SS, 2014; Bauer NC et al., 2015).

ATM's involvement in these processes is based on its

ability to phosphorylate proteins that function in

these pathways. In this way ATM also takes part also

in resolving non-canonical DNA structures that arise



in DNA metabolism, and in regulating other aspects

of genome integrity such as nucleotide metabolism,

the response to replication stress, and resolution of

the occasional conflicts that arise between DNA

damage and the transcription machinery. ATM is not

critical for any of these processes in the same way it

is for the DSB response, but rather contributes to

their regulation (in most cases, their enhancement)

when the need arises (Shiloh Y, 2014; Segal-Raz H

et al., 2011; Zolner AE et al., 2011).

This function of ATM may explain the moderate,

variable sensitivity of ATM-deficient cells to a broad

range of DNA damaging agents. Among them are

UV radiation, alkylating agents, crosslinking agents,

hydrogen peroxide, 4-Nitroquinoline 1-oxide,

phorbol-12-myristate-13-acetate and topoisomerase

1 poisons (Yi M et al., 1990; Ward AJ et al., 1994;

Hoar DI et al., 1976; Paterson MC et al., 1976; Smith

PJ et al., 1980; Mirzayans R et al., 1989; Henderson

EE et al., 1980; Scudiero DA, 1980; Jaspers NG et

al., 1982; Teo IA et al., 1982; Barfknecht TR et al.,

1982; Fedier A et al., 2003; Leonard JC et al., 2004;

Lee JH et al., 2006; Zhang N et al., 1996; Smith PJ

et al., 1989; Alagoz M et al., 2013; Katyal S et al.,

2014; Speit G et al., 2000; Shiloh Y et al., 1985;

Hannan MA et al., 2002).

ATM-deficient cells also exhibit reduced efficiency

in resolving TOP1 (Topoisomerase I) -DNA

covalent intermediates (Alagoz M et al., 2013;

Katyal S et al., 2014).

This ongoing role of ATM is its routine function in

the daily maintenance of genome stability, while its

powerful role in the DSB response is reserved for

when this harmful lesion interferes with the daily life

of a cell. Thus, when ATM is missing, not only is

there markedly reduced response to DSBs, the

ongoing modulation of numerous pathways in

response to occasional stresses becomes suboptimal.

All of these lesions are part of the daily wear and tear

on the genome that contributes to ageing.

An additional role for ATM in genome dynamics

was proposed following evidence that ATM is

involved in shaping the epigenome in neurons by

regulating the localization of the histone deacetylase

4 (HDAC4 Li J et al., 2012; Herrup K et al., 2013;

Herrup K, 2013), targeting the EZH2 component of

the polycomb repressive complex 2 (Li J et al.,

2013), and regulating the levels of 5-

hydroxymethylcytosine in Purkinje cells (Jiang D et

al., 2015).

Oxidative stress/Cellular homeostasis.

Cytoplasmic fraction of ATM ATM's role in

cellular homeostasis is further expanded by its

cytoplasmic fraction. Specifically, cytoplasmic

ATM was found to be associated with peroxisomes

(Watters D et al., 1999; Tripathi DN et al., 2016;

Zhang J et al., 2015) and mitochondria (Valentin-

Vega YA et al., 2012). In view of the evidence of

increased oxidative stress in ATM-deficient cells, it

has long been suspected that ATM senses and

responds to oxidative stress (Gatei M et al., 2001;

Rotman G et al., 1997; Rotman G et al., 1997;

Barzilai A et al., 2002; Watters DJ, 2003; Takao N

et al., 2000; Alexander A et al., 2010). This

conjecture was validated by work from the Paull lab

(Guo Z et al., 2010a), which identified an MRN-

independent mode of ATM activation,

differentiating it from DSB-induced activation,

stimulated by reactive oxygen species (ROS) and

leading to ATM oxidation (Paull TT, 2015; Guo Z et

al., 2010a; Guo Z et al., 2010b; Lee JH et al., 2014).

ATM was also found to be involved specifically in

the protection against oxidative stress induced by

oxidized low-density lipoprotein (Semlitsch M et al.,

2011). It has thus assumed the role of a redox sensor

(Ditch S et al., 2012; Tripathi DN et al., 2016;

Kr+ACY-uuml;ger A et al., 2011). Recently, the first

phospho-proteomic screen was carried out to

identify substrates of ROS-activated ATM (Kozlov

SV et al., 2016). An important arm of the ATM-

mediated response to ROS extends to peroxisomes

(Tripathi DN et al., 2016). Work from the Walker lab

showed that ROS-mediated activation of

peroxisomal ATM leads to ATM-mediated

phosphorylation of LKB and subsequent activation

of AMPK and TSC2, which dampens mTORC1-

mediated signaling, eventually decreasing protein

synthesis and enhancing autophagy (Alexander A et

al., 2010; Tripathi DN et al., 2013; Zhang J et al.,

2013; Alexander A et al., 2010; Alexander A et al.,

2010).

Further work from this lab (Zhang J et al., 2015)

showed that ATM also phosphorylates the

peroxisomal protein PEX5, flagging it for

ubiquitylation and subsequent binding to the

autophagy adapter, SQSTM1 (p62), in the process of

autophagy-associated peroxisome degradation

(pexophagy) - a critical process in peroxisome

homeostasis (Till A et al., 2012).

Mitochondrial fraction of ATM. Still another arm

of the ATM-mediated response to oxidative stress

operates in the mitochondrial fraction of ATM. ATM

is thus emerging also as a regulator of mitochondrial

homeostasis. Evidence is accumulating of its

involvement in mitochondrial function, mitophagy,

and the integrity of mitochondrial DNA (Valentin-

Vega YA et al., 2012; Ambrose M et al., 2007; Eaton

JS et al., 2007; Fu X et al., 2008; Valentin-Vega YA

et al., 2012; D'Souza AD et al., 2013; Sharma NK et

al., 2014) and further work is needed to identify its

substrates in mitochondria and the mechanistic

aspects of its action in this arena.

Links between ATM and the SASP (senescence-

associated secretory phenotype). Several

laboratories recently described direct links between

ATM and the SASP - a cardinal feature of cell

senescence. Work from the Gamble lab (Chen H et

al., 2015) showed that the histone variant



macroH2A.1 is required for full transcriptional

activation of SASP-promoting genes, driving a

positive feedback loop that enhances cell

senescence. This response is countered by a negative

feedback loop that involves ATM activation by

endoplasmic reticulum stress, elevated ROS levels

or DNA damage. ATM's activity is required for the

removal of macroH2A.1 from sites of SASP genes,

thus leading to SASP gene repression. The Elledge

lab identified a major SASP activator - the

transcription factor GATA4 ID, whose stabilization

drives this process (Kang C et al., 2015).

Importantly, the activation of this pathway was

dependent on both ATM and ATR, as was

senescence-associated activation of TP53 and

CDKN2A (p16INK4a). On the other hand, the

Zhang lab (Aird KM et al., 2015) recently showed

that when cell senescence is induced by replication

stress (e.g., following nucleotide deficiency), ATM

inactivation allows the cell to bypass senescence by

shifting cellular metabolism: upon ATM loss, dNTP

levels rise due to up-regulation of the pentose

phosphate pathway, whose key regulator, glucose-6-

phosphate dehydrogenase (G6PD) is under

functional regulation by ATM (Aird KM et al., 2015;

Cosentino C et al., 2011).

Insulin response and lipoprotein metabolism. Other metabolic arenas in which ATM involvement

is gaining attention are insulin response and

lipoprotein metabolism, clinically represented by the

metabolic syndrome. This role of ATM in cellular

physiology was recently thoroughly and

convincingly reviewed (Espach Y et al., 2015).

Briefly, ATM was found to participate in several

signaling pathways mediated by insulin (Yang DQ et

al., 2000; Miles PD et al., 2007; Viniegra JG et al.,

2005; Halaby MJ et al., 2008; Jeong I et al., 2010);

and heterozygosity for Atm null allele in ApoE-

deficient mice was found to aggravate their

metabolic syndrome (Wu D et al., 2005; Schneider

JG et al., 2006; Mercer JR et al., 2010), an effect that

was partly relieved by the mitochondria-targeted

antioxidant MitQ (Mercer JR et al., 2012.

IGF-1 receptor. Another pathway by which ATM

may impact on cellular senescence is the dependence

of IGF1R (IGF-1 receptor) expression on ATM

(Peretz S et al., 2001; Goetz EM et al., 2011; Ching

JK et al., 2013); the mechanism remains to be

elucidated, but ATM impacts on IGF-1-mediated

pathways, including those that affect cellular

senescence (Luo X et al., 2014).

Beta-adrenergic receptor. Another series of

observations assigned ATM a protective role in

cardiac myocyte apoptosis stimulated by +ACY-

beta;-adrenergic receptor and myocardial

remodeling. Loss of Atm in mice induced

myocardial fibrosis and myocyte hypertrophy and

interfered with cardiac remodeling following

myocardial infarction (Foster CR et al., 2011; Foster

CR et al., 2012; Foster CR et al., 2013; Daniel LL et

al., 2014). The mechanistic aspects of these effects

are still unclear, but ATM's apparent involvement in

myocardial homeostasis might be relevant to the

observation of elevated arteriosclerosis in A-T

carriers (Swift M et al., 1983; Su Y et al., 2000).

Homology

Phosphatidylinositol 3-kinase (PI3K)-like proteins,

most closely related to ATR and the DNA-PK

catalytic subunit.

Mutations

The cellular phenotype of A-T represents genome

instability, deficient DNA damage response (DDR),

and elevated oxidative stress, in addition to a

premature senescence component (Shiloh Y et al.,

1982).

Germinal Various types of mutations have been described,

dispersed throughout the gene, and therefore most

patients are compound heterozygotes; most

mutations appear to inactivate the ATM protein by

truncation, large deletions, or annulation of initiation

or termination, although missense mutations have

been described in the PI3 kinase domain and the

leucine zipper motif.

Patients with the severe form of A-T are

homozygous or compound heterozygous for null

ATM alleles. The corresponding mutations usually

lead to truncation of the ATM protein and

subsequently to its loss due to instability of the

truncated derivatives; a smaller portion of the

mutations create amino acid substitutions that

abolish ATM's catalytic activity (Taylor AM et al.,

2015; Gilad S et al., 1996; Sandoval N et al., 1999;

Barone G et al., 2009).

Careful inspection of the neurological symptoms of

A-T patients reveals variability in their age of onset

and rate of progression among patients with different

combinations of null ATM alleles (Taylor AM et al.,

2015; Crawford TO et al., 2000; Alterman N et al.,

2007). Thus, despite the identical outcome in terms

of ATM function, additional genes may affect the

most cardinal symptom of A-T. Other, milder types

of ATM mutations further extend this variability,

and account for forms of the disease with extremely

variable severity and age of onset of symptoms. The

corresponding ATM genotypes are combinations of

hypomorphic alleles or combinations of null and

hypomorphic ones. Many of the latter are leaky

splicing mutations and others are missense

mutations, eventually yielding low amounts of active

ATM (Taylor AM et al., 2015; Alterman N et al.,

2007; Soresina A et al., 2008; Verhagen MM et al.,

2009; Silvestri G et al., 2010; Saunders-Pullman R

et al., 2012; Verhagen MM et al., 2012; Worth PF et

al., 2013; Claes K et al., 2013; M+ACY-eacute;neret



A et al., 2014; Nakamura K et al., 2014; Gilad S et

al., 1998).

Somatic

B A variety of missense somatic, biallelic mutations

were identified in hematologic malignancies, most

notably mantle cell lymphomaand T-

prolymphocytic leukaemia. Missense mutations

outside of the PI3 kinase and leucine zipper domains

have been described among breast cancer patients,

although these mutations have not been found in A-

T patients. Whether these mutations contribute to

breast cancer though not to ataxia-telangiectasia

remains controversial.

Implicated in

Ataxia telangiectasia

Note

Ataxia telangiectasia is a prototype genome

instability syndrome (Perlman SL et al., 2012; Lavin

MF, 2008; Crawford TO, 1998; Chun HH et al.,

2004; Taylor AM et al., 1982; Taylor AM et al.,

2015; Taylor AM, 1978; Butterworth SV et al.,

1986; Kennaugh AA et al., 1986).

Disease

Ataxia telangiectasia is a progressive cerebellar

degenerative disease with telangiectasia,

immunodeficiency, premature aging , cancer risk,

radiosensitivity, and chromosomal instability.

Prognosis

Prognosis is poor: median age at death: 17 years;

survival rarely exceeds 30 years, though survival is

increasing with improved medical care.

Cytogenetics

Spontaneous chromatid/chromosome breaks; non

clonal stable chromosome rearrangements involving

immunoglobulin superfamilly genes e.g.

inv(7)(p14q35); clonal rearrangements.

References Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell. 1996 Jul 12;86(1):159-71

Broeks A, Urbanus JH, Floore AN, Dahler EC, Klijn JG, Rutgers EJ, et al. ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am J Hum Genet. 2000 Feb;66(2):494-500

Brown KD, Ziv Y, Sadanandan SN, Chessa L, Collins FS,

Shiloh Y, Tagle DA. The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not up-regulated following genome damage. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1840-5

Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem. 2001 Nov 9;276(45):42462-7

Chen X, Yang L, Udar N, Liang T, Uhrhammer N, Xu S, Bay JO, Wang Z, Dandakar S, Chiplunkar S, Klisak I, Telatar M, Yang H, Concannon P, Gatti RA. CAND3: a ubiquitously expressed gene immediately adjacent and in opposite transcriptional orientation to the ATM gene at 11q23.1. Mamm Genome. 1997 Feb;8(2):129-33

Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol. 1994 Dec;66(6 Suppl):S177-82

Gorlin RJ et al. - Oxford Monogr Med Genet ..

Greenwell PW, Kronmal SL, Porter SE, Gassenhuber J, Obermaier B, Petes TD. TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell. 1995 ; 82 (5) : 823-829.

Hari KL, Santerre A, Sekelsky JJ, McKim KS, Boyd JB, Hawley RS. The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell. 1995 ; 82 (5) : 815-821.

Janin N, Andrieu N, Ossian K, Laug+ACY-eacute; A, Croquette MF, Griscelli C, Debr+ACY-eacute; M, Bressac-de-Paillerets B, Aurias A, Stoppa-Lyonnet D. Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families. British journal of cancer. 1999 ; 80 (7) : 1042-1045.

Platzer M, Rotman G, Bauer D, Uziel T, Savitsky K, Bar-Shira A, Gilad S, Shiloh Y, Rosenthal A. Ataxia-telangiectasia locus: sequence analysis of 184 kb of human genomic DNA containing the entire ATM gene. Genome research. 1997 ; 7 (6) : 592-605.

Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y, Rotman G. The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Human molecular genetics. 1995 ; 4 (11) : 2025-2032.

Shiloh Y. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annual review of genetics. 1997 ; 31 : 635-662.

Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A, James MR, Lichter P, D+ACY-ouml;hner H. Biallelic mutations in the ATM gene in T-prolymphocytic leukemia. Nature medicine. 1997 ; 3 (10) : 1155-1159.

Telatar M, Teraoka S, Wang Z, Chun HH, et al. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. American journal of human genetics. 1998 ; 62 (1) : 86-97.

Vorechovsk+ACY-yacute; I, Luo L, Dyer MJ, Catovsky D, Amlot PL, Yaxley JC, Foroni L, Hammarstr+ACY-ouml;m L, Webster AD, Yuille MA. Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nature genetics. 1997 ; 17 (1) : 96-99.

Westphal CH. Cell-cycle signaling: Atm displays its many talents. Current biology : CB. 1997 ; 7 (12) : R789-R792.

Xie G, Habbersett RC, Jia Y, Peterson SR, Lehnert BE, Bradbury EM, D'Anna JA. Requirements for p53 and the ATM gene product in the regulation of G1/S and S phase

checkpoints. Oncogene. 1998 ; 16 (6) : 721-736.

Zakian VA. ATM-related genes: what do they tell us about functions of the human gene? Cell. 1995 ; 82 (5) : 685-687.

Ziv Y, Bar-Shira A, Pecker I, Russell P, Jorgensen TJ, Tsarfati I, Shiloh Y. Recombinant ATM protein complements the cellular A-T phenotype. Oncogene. 1997 ; 15 (2) : 159-167.



Perlman SL, Boder Deceased E, Sedgewick RP, Gatti RA. Ataxia-telangiectasia Handb Clin Neurol 2012;103:307-32

Lavin MF. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer Nat Rev Mol Cell Biol 2008 Oct;9(10):759-69

Crawford TO. Ataxia telangiectasia Semin Pediatr Neurol 1998 Dec;5(4):287-94

Chun HH, Gatti RA. Ataxia-telangiectasia, an evolving phenotype DNA Repair (Amst) 2004 Aug-Sep;3(8-9):1187-96

Nissenkorn A, Levy-Shraga Y, Banet-Levi Y, Lahad A, Sarouk I, Modan-Moses D. Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort Pediatr Res 2016 Jun;79(6):889-94

Taylor AM, Lam Z, Last JI, Byrd PJ. Ataxia telangiectasia: more variation at clinical and cellular levels Clin Genet 2015 Mar;87(3):199-208

Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NG, Lange K, et al. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23 Nature 1988 Dec 8;336(6199):577-80

Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase Science 1995 Jun 23;268(5218):1749-53

Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y, Rotman G. The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species Hum Mol Genet 1995 Nov;4(11):2025-32

Ziv Y, Bar-Shira A, Pecker I, Russell P, Jorgensen TJ, Tsarfati I, Shiloh Y. Recombinant ATM protein complements the cellular A-T phenotype Oncogene 1997 Jul 10;15(2):159-67

Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more Nat Rev Mol Cell Biol 2013 Apr;14(4):197-210

Shiloh Y. ATM: expanding roles as a chief guardian of genome stability Exp Cell Res 2014 Nov 15;329(1):154-61

Guleria A, Chandna S. ATM kinase: Much more than a DNA damage responsive protein DNA Repair (Amst) 2016 Mar;39:1-20

Ditch S, Paull TT. The ATM protein kinase and cellular redox signaling: beyond the DNA damage response Trends Biochem Sci 2012 Jan;37(1):15-22

BODER E, SEDGWICK RP. Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection Pediatrics 1958 Apr;21(4):526-54

SEDGWICK RP, BODER E. Progressive ataxia in childhood with particular reference to ataxia-telangiectasia Neurology 1960 Jul;10:705-15

Boder E. Ataxia-telangiectasia: an overview Kroc Found Ser 1985;19:1-63

Crawford TO, Mandir AS, Lefton-Greif MA, Goodman SN, Goodman BK, Sengul H, Lederman HM. Quantitative neurologic assessment of ataxia-telangiectasia Neurology 2000 Apr 11;54(7):1505-9

Gatti RA. Ataxia-telangiectasia Dermatol Clin 1995 Jan;13(1):1-6

Verhagen MM, Martin JJ, van Deuren M, Ceuterick-de Groote C, Weemaes CM, Kremer BH, Taylor MA, Willemsen MA, Lammens M. Neuropathology in classical and variant ataxia-telangiectasia Neuropathology 2012 Jun;32(3):234-44

Lefton-Greif MA, Crawford TO, Winkelstein JA, Loughlin GM, Koerner CB, Zahurak M, Lederman HM. Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia J Pediatr 2000 Feb;136(2):225-31

Bhatt JM, Bush A, van Gerven M, Nissenkorn A, Renke M, Yarlett L, Taylor M, Tonia T, Warris A, Zielen S, Zinna S, Merkus PJ; European Respiratory Society. ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia Eur Respir Rev

Vinters HV, Gatti RA, Rakic P. Sequence of cellular events in cerebellar ontogeny relevant to expression of neuronal abnormalities in ataxia-telangiectasia Kroc Found Ser 1985;19:233-55

Gatti RA, Vinters HV. Cerebellar pathology in ataxia-telangiectasia: the significance of basket cells Kroc Found Ser 1985;19:225-32

Greenberger S, Berkun Y, Ben-Zeev B, Levi YB, Barziliai A, Nissenkorn A. Dermatologic manifestations of ataxia-telangiectasia syndrome J Am Acad Dermatol 2013 Jun;68(6):932-6

Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM. Immunodeficiency and infections in ataxia-telangiectasia J Pediatr 2004 Apr;144(4):505-11

Gatti RA, Bick M, Tam CF, Medici MA, Oxelius VA, Holland M, Goldstein AL, Boder E. Ataxia-Telangiectasia: a multiparameter analysis of eight families Clin Immunol Immunopathol 1982 May;23(2):501-16

Weaver M, Gatti RA. Lymphocyte subpopulations in ataxia-telangiectasia Kroc Found Ser 1985;19:309-14

H+ACY-auml;rtlova A, Erttmann SF, Raffi FA, Schmalz AM, Resch U, Anugula S, Lienenklaus S, Nilsson LM, Kr+ACY-ouml;ger A, Nilsson JA, Ek T, Weiss S, Gekara NO. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity Immunity 2015 Feb 17;42(2):332-43

Loeb DM, Lederman HM, Winkelstein JA. Lymphoid malignancy as a presenting sign of ataxia-telangiectasia J Pediatr Hematol Oncol 2000 Sep-Oct;22(5):464-7

Murphy RC, Berdon WE, Ruzal-Shapiro C, Hall EJ, Kornecki A, Daneman A, Brunelle F, Campbell JB. Malignancies in pediatric patients with ataxia telangiectasia Pediatr Radiol 1999 Apr;29(4):225-30

Olsen JH, Hahnemann JM, B+ACY-oslash;rresen-Dale AL, Br+ACY-oslash;ndum-Nielsen K, Hammarstr+ACY-ouml;m L, Kleinerman R, K+ACY-aelig;ri+ACY-auml;inen H, L+ACY-ouml;nnqvist T, Sankila R, Seersholm N, Tretli S,

Yuen J, Boice JD Jr, Tucker M. Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries J Natl Cancer Inst 2001 Jan 17;93(2):121-7

Taylor AM, Edwards MJ. Malignancy, DNA damage and chromosomal aberrations in ataxia telangiectasia IARC Sci Publ 1982;(39):119-26

Ehlayel M, Soliman A, De Sanctis V. Linear growth and endocrine function in children with ataxia telangiectasia Indian J Endocrinol Metab 2014 Nov;18(Suppl 1):S93-6

Voss S, Pietzner J, Hoche F, Taylor AM, Last JI, Schubert R, Zielen S. Growth retardation and growth hormone



deficiency in patients with Ataxia telangiectasia Growth Factors 2014 Jun;32(3-4):123-9

Pommerening H, van Dullemen S, Kieslich M, Schubert R, Zielen S, Voss S. Body composition, muscle strength and hormonal status in patients with ataxia telangiectasia: a cohort study Orphanet J Rare Dis 2015 Dec 9;10:155

Ehlayel M, Soliman A, De Sanctis V. Linear growth and endocrine function in children with ataxia telangiectasia Indian J Endocrinol Metab 2014 Nov;18(Suppl 1):S93-6

Nissenkorn A, Levy-Shraga Y, Banet-Levi Y, Lahad A, Sarouk I, Modan-Moses D. Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort Pediatr Res 2016 Jun;79(6):889-94

Schalch DS, McFarlin DE, Barlow MH. An unusual form of diabetes mellitus in ataxia telangiectasia N Engl J Med 1970 Jun 18;282(25):1396-402

Morrell D, Chase CL, Kupper LL, Swift M. Diabetes mellitus in ataxia-telangiectasia, Fanconi anemia, xeroderma pigmentosum, common variable immune deficiency, and severe combined immune deficiency families Diabetes 1986 Feb;35(2):143-7

Blevins LS Jr, Gebhart SS. Insulin-resistant diabetes mellitus in a black woman with ataxia-telangiectasia South Med J 1996 Jun;89(6):619-21

Taylor AM, Lam Z, Last JI, Byrd PJ. Ataxia telangiectasia: more variation at clinical and cellular levels Clin Genet 2015 Mar;87(3):199-208

Taylor AM. Unrepaired DNA strand breaks in irradiated ataxia telangiectasia lymphocytes suggested from cytogenetic observations Mutat Res 1978 Jun;50(3):407-18

Butterworth SV, Taylor AM. A subpopulation of t(2;14)(p11;q32) cells in ataxia telangiectasia B lymphocytes Hum Genet 1986 Aug;73(4):346-9

Kennaugh AA, Butterworth SV, Hollis R, Baer R, Rabbitts TH, Taylor AM. The chromosome breakpoint at 14q32 in an ataxia telangiectasia t(14;14) T cell clone is different from the 14q32 breakpoint in Burkitts and an inv(14) T cell lymphoma Hum Genet 1986 Jul;73(3):254-9

Gotoff SP, Amirmokri E, Liebner EJ. Ataxia telangiectasia Neoplasia, untoward response to x-irradiation, and tuberous sclerosis Am J Dis Child

Morgan JL, Holcomb TM, Morrissey RW. Radiation reaction in ataxia telangiectasia Am J Dis Child 1968 Nov;116(5):557-8

Taylor AM, Harnden DG, Arlett CF, Harcourt SA, Lehmann AR, Stevens S, Bridges BA. Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity Nature 1975 Dec 4;258(5534):427-9

Taylor AM, Rosney CM, Campbell JB. Unusual sensitivity of ataxia telangiectasia cells to bleomycin Cancer Res 1979 Mar;39(3):1046-50

Shiloh Y, Tabor E, Becker Y. Cellular hypersensitivity to neocarzinostatin in ataxia-telangiectasia skin fibroblasts Cancer Res 1982 Jun;42(6):2247-9

Shiloh Y, Tabor E, Becker Y. Abnormal response of ataxia-telangiectasia cells to agents that break the deoxyribose moiety of DNA via a targeted free radical mechanism Carcinogenesis 1983 Oct;4(10):1317-22

Djuzenova CS, Schindler D, Stopper H, Hoehn H, Flentje M, Oppitz U. Identification of ataxia telangiectasia heterozygotes, a cancer-prone population, using the single-

cell gel electrophoresis (Comet) assay Lab Invest 1999 Jun;79(6):699-705

Taylor AM, Butterworth SV. Clonal evolution of T-cell chronic lymphocytic leukaemia in a patient with ataxia telangiectasia Int J Cancer 1986 Apr 15;37(4):511-6

Heppell A, Butterworth SV, Hollis RJ, Kennaugh AA, Beatty DW, Taylor AM. Breakage of the T cell receptor alpha chain locus in non malignant clones from patients with ataxia telangiectasia Hum Genet 1988 Aug;79(4):360-4

Kojis TL, Gatti RA, Sparkes RS. The cytogenetics of ataxia telangiectasia Cancer Genet Cytogenet 1991 Oct 15;56(2):143-56

Pandita TK, Pathak S, Geard CR. Chromosome end associations, telomeres and telomerase activity in ataxia telangiectasia cells Cytogenet Cell Genet 1995;71(1):86-93

Smilenov LB, Dhar S, Pandita TK. Altered telomere nuclear matrix interactions and nucleosomal periodicity in ataxia telangiectasia cells before and after ionizing radiation treatment Mol Cell Biol 1999 Oct;19(10):6963-71

Wood LD, Halvorsen TL, Dhar S, Baur JA, Pandita RK, Wright WE, Hande MP, Calaf G, Hei TK, Levine F, Shay JW, Wang JJ, Pandita TK. Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression Oncogene 2001 Jan 18;20(3):278-88

Metcalfe JA, Parkhill J, Campbell L, Stacey M, Biggs P, Byrd PJ, Taylor AM. Accelerated telomere shortening in ataxia telangiectasia Nat Genet 1996 Jul;13(3):350-3

Vaziri H. Critical telomere shortening regulated by the ataxia-telangiectasia gene acts as a DNA damage signal leading to activation of p53 protein and limited life-span of human diploid fibroblasts A review Biochemistry (Mosc)

Shiloh Y, Tabor E, Becker Y. Colony-forming ability of ataxia-telangiectasia skin fibroblasts is an indicator of their early senescence and increased demand for growth factors Exp Cell Res 1982 Jul;140(1):191-9

Reichenbach J, Schubert R, Schindler D, M+ACY-uuml;ller K, B+ACY-ouml;hles H, Zielen S. Elevated oxidative stress in patients with ataxia telangiectasia Antioxid Redox Signal 2002 Jun;4(3):465-9

Gatei M, Shkedy D, Khanna KK, Uziel T, Shiloh Y, Pandita TK, Lavin MF, Rotman G. Ataxia-telangiectasia: chronic activation of damage-responsive functions is reduced by alpha-lipoic acid Oncogene 2001 Jan 18;20(3):289-94

Lee SA, Dritschilo A, Jung M. Role of ATM in oxidative stress-mediated c-Jun phosphorylation in response to

ionizing radiation and CdCl2 J Biol Chem 2001 Apr 13;276(15):11783-90

Ludwig LB, Valiati VH, Palazzo RP, Jardim LB, da Rosa DP, Bona S, Rodrigues G, Marroni NP, Pr+ACY-aacute; D, Maluf SW. Chromosome instability and oxidative stress markers in patients with ataxia telangiectasia and their parents Biomed Res Int 2013;2013:762048

Barlow C, Dennery PA, Shigenaga MK, Smith MA, Morrow JD, Roberts LJ 2nd, Wynshaw-Boris A, Levine RL. Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs Proc Natl Acad Sci U S A 1999 Aug 17;96(17):9915-9

Kamsler A, Daily D, Hochman A, Stern N, Shiloh Y, Rotman G, Barzilai A. Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of



brains from Atm-deficient mice Cancer Res 2001 Mar 1;61(5):1849-54

Gage BM, Alroy D, Shin CY, Ponomareva ON, Dhar S, Sharma GG, Pandita TK, Thayer MJ, Turker MS. Spontaneously immortalized cell lines obtained from adult Atm null mice retain sensitivity to ionizing radiation and exhibit a mutational pattern suggestive of oxidative stress Oncogene 2001 Jul 19;20(32):4291-7

Ziv S, Brenner O, Amariglio N, Smorodinsky NI, Galron R, Carrion DV, Zhang W, Sharma GG, Pandita RK, Agarwal M, Elkon R, Katzin N, Bar-Am I, Pandita TK, Kucherlapati R, Rechavi G, Shiloh Y, Barzilai A. Impaired genomic stability and increased oxidative stress exacerbate different features of Ataxia-telangiectasia Hum Mol Genet 2005 Oct 1;14(19):2929-43

Chen P, Peng C, Luff J, Spring K, Watters D, Bottle S, Furuya S, Lavin MF. Oxidative stress is responsible for deficient survival and dendritogenesis in purkinje neurons from ataxia-telangiectasia mutated mutant mice J Neurosci 2003 Dec 10;23(36):11453-60

Reliene R, Fischer E, Schiestl RH. Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice Cancer Res 2004 Aug 1;64(15):5148-53

Reliene R, Schiestl RH. Antioxidants suppress lymphoma and increase longevity in Atm-deficient mice J Nutr 2007 Jan;137(1 Suppl):229S-232S

Liu N, Stoica G, Yan M, Scofield VL, Qiang W, Lynn WS, Wong PK. ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes Lab Invest 2005 Dec;85(12):1471-80

McDonald CJ, Ostini L, Wallace DF, John AN, Watters DJ, Subramaniam VN. Iron loading and oxidative stress in the Atm-/- mouse liver Am J Physiol Gastrointest Liver Physiol 2011 Apr;300(4):G554-60

Yi M, Rosin MP, Anderson CK. Response of fibroblast cultures from ataxia-telangiectasia patients to oxidative stress Cancer Lett 1990 Oct 8;54(1-2):43-50

Ward AJ, Olive PL, Burr AH, Rosin MP. Response of fibroblast cultures from ataxia-telangiectasia patients to reactive oxygen species generated during inflammatory reactions Environ Mol Mutagen 1994;24(2):103-11

Exley AR, Buckenham S, Hodges E, Hallam R, Byrd P, Last J, Trinder C, Harris S, Screaton N, Williams AP, Taylor AM, Shneerson JM. Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia Clin Immunol 2011 Jul;140(1):26-36

Carney EF, Srinivasan V, Moss PA, Taylor AM. Classical ataxia telangiectasia patients have a congenitally aged immune system with high expression of CD95 J Immunol 2012 Jul 1;189(1):261-8

Barzilai A, Schumacher B, Shiloh Y. Genome instability: Linking ageing and brain degeneration Mech Ageing Dev 2016 Mar 31

Weiss B, Krauthammer A, Soudack M, Lahad A, Sarouk I, Somech R, Heimer G, Ben-Zeev B, Nissenkorn A. Liver Disease in Pediatric Patients With Ataxia Telangiectasia: A Novel Report J Pediatr Gastroenterol Nutr 2016 Apr;62(4):550-5

Sadighi Akha AA, Humphrey RL, Winkelstein JA, Loeb DM, Lederman HM. Oligo-/monoclonal gammopathy and hypergammaglobulinemia in ataxia-telangiectasia A study of 90 patients Medicine (Baltimore)

Reed WB, Epstein WL, Boder E, Sedgwick R. Cutaneous manifestations of ataxia-telangiectasia JAMA 1966 Feb 28;195(9):746-53

McGrath-Morrow SA, Collaco JM, Detrick B, Lederman HM. Serum Interleukin-6 Levels and Pulmonary Function in Ataxia-Telangiectasia J Pediatr 2016 Apr;171:256-61

Lin DD, Barker PB, Lederman HM, Crawford TO. Cerebral abnormalities in adults with ataxia-telangiectasia AJNR Am J Neuroradiol 2014 Jan;35(1):119-23

Xia SJ, Shammas MA, Shmookler Reis RJ. Reduced telomere length in ataxia-telangiectasia fibroblasts Mutat Res 1996 Sep 2;364(1):1-11

Smilenov LB, Morgan SE, Mellado W, Sawant SG, Kastan MB, Pandita TK. Influence of ATM function on telomere metabolism Oncogene 1997 Nov 27;15(22):2659-65

Webb CJ, Wu Y, Zakian VA. DNA repair at telomeres: keeping the ends intact Cold Spring Harb Perspect Biol 2013 Jun 1;5(6)

Doksani Y, de Lange T. The role of double-strand break repair pathways at functional and dysfunctional telomeres Cold Spring Harb Perspect Biol 2014 Sep 16;6(12):a016576

Arnoult N, Karlseder J. Complex interactions between the DNA-damage response and mammalian telomeres Nat Struct Mol Biol 2015 Nov;22(11):859-66

Uziel T, Savitsky K, Platzer M, Ziv Y, Helbitz T, Nehls M, Boehm T, Rosenthal A, Shiloh Y, Rotman G. Genomic Organization of the ATM gene Genomics 1996 Apr 15;33(2):317-20

Platzer M, Rotman G, Bauer D, Uziel T, Savitsky K, Bar-Shira A, Gilad S, Shiloh Y, Rosenthal A. Ataxia-telangiectasia locus: sequence analysis of 184 kb of human genomic DNA containing the entire ATM gene Genome Res 1997 Jun;7(6):592-605

Gilad S, Khosravi R, Shkedy D, Uziel T, Ziv Y, Savitsky K, Rotman G, Smith S, Chessa L, Jorgensen TJ, Harnik R, Frydman M, Sanal O, Portnoi S, Goldwicz Z, Jaspers NG, Gatti RA, Lenoir G, Lavin MF, Tatsumi K, Wegner RD, Shiloh Y, Bar-Shira A. Predominance of null mutations in ataxia-telangiectasia Hum Mol Genet 1996 Apr;5(4):433-9

Barone G, Groom A, Reiman A, Srinivasan V, Byrd PJ, Taylor AM. Modeling ATM mutant proteins from missense changes confirms retained kinase activity Hum Mutat 2009 Aug;30(8):1222-30

Alterman N, Fattal-Valevski A, Moyal L, Crawford TO, Lederman HM, Ziv Y, Shiloh Y. Ataxia-telangiectasia: mild neurological presentation despite null ATM mutation and severe cellular phenotype Am J Med Genet A 2007 Aug 15;143A(16):1827-34

Soresina A, Meini A, Lougaris V, Cattaneo G, Pellegrino S, Piane M, Darra F, Plebani A. Different clinical and immunological presentation of ataxia-telangiectasia within

the same family Neuropediatrics 2008 Feb;39(1):43-5

Verhagen MM, Abdo WF, Willemsen MA, Hogervorst FB, Smeets DF, Hiel JA, Brunt ER, van Rijn MA, Majoor Krakauer D, Oldenburg RA, Broeks A, Last JI, van't Veer LJ, Tijssen MA, Dubois AM, Kremer HP, Weemaes CM, Taylor AM, van Deuren M. Clinical spectrum of ataxia-telangiectasia in adulthood Neurology 2009 Aug 11;73(6):430-7

Silvestri G, Masciullo M, Piane M, Savio C, Modoni A, Santoro M, Chessa L. Homozygosity for c 6325T+ACY-gt;G transition in the ATM gene causes an atypical, late-onset



variant form of ataxia-telangiectasia J Neurol 2010 Oct;257(10):1738-40

Saunders-Pullman R, Raymond D, Stoessl AJ, Hobson D, Nakamura K, Pullman S, Lefton D, Okun MS, Uitti R, Sachdev R, Stanley K, San Luciano M, Hagenah J, Gatti R, Ozelius LJ, Bressman SB. Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites Neurology 2012 Feb 28;78(9):649-57

Verhagen MM, Last JI, Hogervorst FB, et al. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study Hum Mutat 2012 Mar;33(3):561-71

Worth PF, Srinivasan V, Smith A, Last JI, Wootton LL, Biggs PM, Davies NP, Carney EF, Byrd PJ, Taylor AM. Very mild presentation in adult with classical cellular phenotype of ataxia telangiectasia Mov Disord 2013 Apr;28(4):524-8

Claes K, Depuydt J, Taylor AM, Last JI, Baert A, Schietecatte P, Vandersickel V, Poppe B, De Leeneer K, D'Hooghe M, Vral A. Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives Neuromolecular Med 2013 Sep;15(3):447-57

M+ACY-eacute;neret A, Ahmar-Beaugendre Y, Rieunier G, Mahlaoui N, Gaymard B, Apartis E, Tranchant C, Rivaud-P+ACY-eacute;choux S, Degos B, Benyahia B, Suarez F, Maisonobe T, Koenig M, Durr A, Stern MH, Dubois d'Enghien C, Fischer A, Vidailhet M, Stoppa-Lyonnet D, Grabli D, Anheim M. The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia Neurology 2014 Sep 16;83(12):1087-95

Nakamura K, Fike F, Haghayegh S, Saunders-Pullman R, Dawson AJ, D+ACY-ouml;rk T, Gatti RA. A-TWinnipeg: Pathogenesis of rare ATM missense mutation c 6200C+ACY-gt;A with decreased protein expression and downstream signaling, early-onset dystonia, cancer, and life-threatening radiotoxicity Mol Genet Genomic Med

Gilad S, Chessa L, Khosravi R, Russell P, Galanty Y, Piane M, Gatti RA, Jorgensen TJ, Shiloh Y, Bar-Shira A. Genotype-phenotype relationships in ataxia-telangiectasia and variants Am J Hum Genet 1998 Mar;62(3):551-61

Shiloh Y. ATM: expanding roles as a chief guardian of genome stability Exp Cell Res 2014 Nov 15;329(1):154-61

Cremona CA, Behrens A. ATM signalling and cancer Oncogene 2014 Jun 26;33(26):3351-60

Ambrose M, Gatti RA. Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions Blood 2013 May 16;121(20):4036-45

Espach Y, Lochner A, Strijdom H, Huisamen B. ATM

protein kinase signaling, type 2 diabetes and cardiovascular disease Cardiovasc Drugs Ther 2015 Feb;29(1):51-8

Awasthi P, Foiani M, Kumar A. ATM and ATR signaling at a glance J Cell Sci 2016 Mar 15;129(6):1285

Lovejoy CA, Cortez D. Common mechanisms of PIKK regulation DNA Repair (Amst) 2009 Sep 2;8(9):1004-8

Bareti+ACY-cacute; D, Williams RL. PIKKs--the solenoid nest where partners and kinases meet Curr Opin Struct Biol 2014 Dec;29:134-42

Alayev A, Holz MK. mTOR signaling for biological control and cancer J Cell Physiol 2013 Aug;228(8):1658-64

Cornu M, Albert V, Hall MN. mTOR in aging, metabolism, and cancer Curr Opin Genet Dev 2013 Feb;23(1):53-62

Davis AJ, Chen BP, Chen DJ. DNA-PK: a dynamic enzyme in a versatile DSB repair pathway DNA Repair (Amst) 2014 May;17:21-9

Jette N, Lees-Miller SP. The DNA-dependent protein kinase: A multifunctional protein kinase with roles in DNA double strand break repair and mitosis Prog Biophys Mol Biol 2015 Mar;117(2-3):194-205

Yamashita A. Role of SMG-1-mediated Upf1 phosphorylation in mammalian nonsense-mediated mRNA decay Genes Cells 2013 Mar;18(3):161-75

Errico A, Costanzo V. Mechanisms of replication fork protection: a safeguard for genome stability Crit Rev Biochem Mol Biol 2012 May-Jun;47(3):222-35

Mar+ACY-eacute;chal A, Zou L. DNA damage sensing by the ATM and ATR kinases Cold Spring Harb Perspect Biol 2013 Sep 1;5(9)

Awasthi P, Foiani M, Kumar A. ATM and ATR signaling at a glance J Cell Sci 2016 Mar 15;129(6):1285

Sirbu BM, Cortez D. DNA damage response: three levels of DNA repair regulation Cold Spring Harb Perspect Biol 2013 Aug 1;5(8):a012724

Thompson LH. Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: the molecular choreography Mutat Res 2012 Oct-Dec;751(2):158-246

Gobbini E, Cesena D, Galbiati A, Lockhart A, Longhese MP. Interplays between ATM/Tel1 and ATR/Mec1 in sensing and signaling DNA double-strand breaks DNA Repair (Amst) 2013 Oct;12(10):791-9

Chen BP, Li M, Asaithamby A. New insights into the roles of ATM and DNA-PKcs in the cellular response to oxidative stress Cancer Lett 2012 Dec 31;327(1-2):103-10

McKinnon PJ. ATM and the molecular pathogenesis of ataxia telangiectasia Annu Rev Pathol 2012;7:303-21

Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress Curr Biol 2014 May 19;24(10):R453-62

Borde V, de Massy B. Programmed induction of DNA double strand breaks during meiosis: setting up communication between DNA and the chromosome structure Curr Opin Genet Dev 2013 Apr;23(2):147-55

Lange J, Pan J, Cole F, Thelen MP, Jasin M, Keeney S. ATM controls meiotic double-strand-break formation Nature 2011 Oct 16;479(7372):237-40

Alt FW, Zhang Y, Meng FL, Guo C, Schwer B.

Mechanisms of programmed DNA lesions and genomic instability in the immune system Cell 2013 Jan 31;152(3):417-29

Shibata A, Jeggo PA. DNA double-strand break repair in a cellular context Clin Oncol (R Coll Radiol) 2014 May;26(5):243-9

Chapman JR, Taylor MR, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice Mol Cell 2012 Aug 24;47(4):497-510

Jasin M, Rothstein R. Repair of strand breaks by homologous recombination Cold Spring Harb Perspect Biol 2013 Nov 1;5(11):a012740

Radhakrishnan SK, Jette N, Lees-Miller SP. Non-homologous end joining: emerging themes and unanswered questions DNA Repair (Amst) 2014 May;17:2-8



Goodarzi AA, Jeggo PA. The repair and signaling responses to DNA double-strand breaks Adv Genet 2013;82:1-45

Panier S, Durocher D. Push back to respond better: regulatory inhibition of the DNA double-strand break response Nat Rev Mol Cell Biol 2013 Oct;14(10):661-72

Polo SE, Jackson SP. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications Genes Dev 2011 Mar 1;25(5):409-33

Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more Nat Rev Mol Cell Biol 2013 Apr;14(4):197-210

Bhatti S, Kozlov S, Farooqi AA, Naqi A, Lavin M, Khanna KK. ATM protein kinase: the linchpin of cellular defenses to stress Cell Mol Life Sci 2011 Sep;68(18):2977-3006

Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation Nature 2003 Jan 30;421(6922):499-506

Kozlov SV, Graham ME, Peng C, Chen P, Robinson PJ, Lavin MF. Involvement of novel autophosphorylation sites in ATM activation EMBO J 2006 Aug 9;25(15):3504-14

Bensimon A, Schmidt A, Ziv Y, Elkon R, Wang SY, Chen DJ, Aebersold R, Shiloh Y. ATM-dependent and -independent dynamics of the nuclear phosphoproteome after DNA damage Sci Signal 2010 Dec 7;3(151):rs3

Sun Y, Xu Y, Roy K, Price BD. DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity Mol Cell Biol 2007 Dec;27(24):8502-9

Kaidi A, Jackson SP. KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling Nature 2013 Jun 6;498(7452):70-4

Paull TT. Mechanisms of ATM Activation Annu Rev Biochem 2015;84:711-38

Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage Science 2007 May 25;316(5828):1160-6

Mu JJ, Wang Y, Luo H, Leng M, Zhang J, Yang T, Besusso D, Jung SY, Qin J. A proteomic analysis of ataxia telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) substrates identifies the ubiquitin-proteasome system as a regulator for DNA damage checkpoints J Biol Chem 2007 Jun 15;282(24):17330-4

Bensimon A, Aebersold R, Shiloh Y. Beyond ATM: the protein kinase landscape of the DNA damage response FEBS Lett 2011 Jun 6;585(11):1625-39

Khoronenkova SV, Dianov GL. ATM prevents DSB formation by coordinating SSB repair and cell cycle progression Proc Natl Acad Sci U S A 2015 Mar 31;112(13):3997-4002

Wallace SS. Base excision repair: a critical player in many games DNA Repair (Amst) 2014 Jul;19:14-26

Bauer NC, Corbett AH, Doetsch PW. The current state of eukaryotic DNA base damage and repair Nucleic Acids Res 2015 Dec 2;43(21):10083-101

Segal-Raz H, Mass G, Baranes-Bachar K, et al. ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair EMBO Rep 2011 Jul 1;12(7):713-9

Zolner AE, Abdou I, Ye R, Mani RS, et al. Phosphorylation of polynucleotide kinase/ phosphatase by DNA-dependent protein kinase and ataxia-telangiectasia mutated regulates its association with sites of DNA damage Nucleic Acids Res 2011 Nov;39(21):9224-37

Hoar DI, Sargent P. Chemical mutagen hypersensitivity in ataxia telangiectasia Nature 1976 Jun 17;261(5561):590-2

Paterson MC, Smith BP, Lohman PH, Anderson AK, Fishman L. Defective excision repair of gamma-ray-damaged DNA in human (ataxia telangiectasia) fibroblasts Nature 1976 Apr 1;260(5550):444-7

Smith PJ, Paterson MC. Defective DNA repair and increased lethality in ataxia telangiectasia cells exposed to 4-nitroquinoline-1-oxide Nature 1980 Oct 23;287(5784):747-9

Mirzayans R, Smith BP, Paterson MC. Hypersensitivity to cell killing and faulty repair of 1-beta-D-arabinofuranosylcytosine-detectable sites in human (ataxia-telangiectasia) fibroblasts treated with 4-nitroquinoline 1-oxide Cancer Res 1989 Oct 15;49(20):5523-9

Henderson EE, Ribecky R. DNA repair in lymphoblastoid cell lines established from human genetic disorders Chem Biol Interact 1980 Dec;33(1):63-81

Scudiero DA. Decreased DNA repair synthesis and defective colony-forming ability of ataxia telangiectasia fibroblast cell strains treated with N-methyl-N'-nitro-N-nitrosoguanidine Cancer Res 1980 Apr;40(4):984-90

Jaspers NG, de Wit J, Regulski MR, Bootsma D. Abnormal regulation of DNA replication and increased lethality in ataxia telangiectasia cells exposed to carcinogenic agents Cancer Res 1982 Jan;42(1):335-41

Teo IA, Arlett CF. The response of a variety of human fibroblast cell strains to the lethal effects of alkylating agents Carcinogenesis 1982;3(1):33-7

Barfknecht TR, Little JB. Hypersensitivity of ataxia telangiectasia skin fibroblasts to DNA alkylating agents Mutat Res 1982 Jun;94(2):369-82

Fedier A, Schlamminger M, Schwarz VA, Haller U, Howell SB, Fink D. Loss of atm sensitises p53-deficient cells to topoisomerase poisons and antimetabolites Ann Oncol 2003 Jun;14(6):938-45

Leonard JC, Mullinger AM, Schmidt J, Cordell HJ, Johnson RT. Genome instability in ataxia telangiectasia (A-T) families: camptothecin-induced damage to replicating DNA

discriminates between obligate A-T heterozygotes, A-T homozygotes and controls Biosci Rep 2004 Dec;24(6):617-29

Lee JH, Kim KH, Morio T, Kim H. Ataxia-telangiectasia-mutated-dependent activation of Ku in human fibroblasts exposed to hydrogen peroxide Ann N Y Acad Sci 2006 Dec;1091:76-82

Zhang N, Song Q, Lu H, Lavin MF. Induction of p53 and increased sensitivity to cisplatin in ataxia-telangiectasia cells Oncogene 1996 Aug 1;13(3):655-9

Smith PJ, Makinson TA, Watson JV. Enhanced sensitivity to camptothecin in ataxia-telangiectasia cells and its relationship with the expression of DNA topoisomerase I Int J Radiat Biol 1989 Feb;55(2):217-31

Alagoz M, Chiang SC, Sharma A, El-Khamisy SF. ATM deficiency results in accumulation of DNA-topoisomerase I covalent intermediates in neural cells PLoS One 2013;8(4):e58239



Katyal S, Lee Y, Nitiss KC, Downing SM, Li Y, Shimada M, Zhao J, Russell HR, Petrini JH, Nitiss JL, McKinnon PJ. Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes Nat Neurosci 2014 Jun;17(6):813-21

Speit G, Trenz K, Sch+ACY-uuml;tz P, Bendix R, D+ACY-ouml;rk T. Mutagen sensitivity of human lymphoblastoid cells with a BRCA1 mutation in comparison to ataxia telangiectasia heterozygote cells Cytogenet Cell Genet 2000;91(1-4):261-6

Shiloh Y, Tabor E, Becker Y. Cells from patients with ataxia telangiectasia are abnormally sensitive to the cytotoxic effect of a tumor promoter, phorbol-12-myristate-13-acetate Mutat Res 1985 Apr;149(2):283-6

Hannan MA, Hellani A, Al-Khodairy FM, et al. Deficiency in the repair of UV-induced DNA damage in human skin fibroblasts compromised for the ATM gene Carcinogenesis 2002 Oct;23(10):1617-24

Li J, Chen J, Ricupero CL, Hart RP, Schwartz MS, Kusnecov A, Herrup K. Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia Nat Med 2012 May;18(5):783-90

Herrup K, Li J, Chen J. The role of ATM and DNA damage in neurons: upstream and downstream connections DNA Repair (Amst) 2013 Aug;12(8):600-4

Herrup K. ATM and the epigenetics of the neuronal genome Mech Ageing Dev 2013 Oct;134(10):434-9

Li J, Hart RP, Mallimo EM, Swerdel MR, Kusnecov AW, Herrup K. EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia Nat Neurosci 2013 Dec;16(12):1745-53

Jiang D, Zhang Y, Hart RP, Chen J, Herrup K, Li J. Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency Brain 2015 Dec;138(Pt 12):3520-36

Watters D, Kedar P, Spring K, Bjorkman J, Chen P, Gatei M, Birrell G, Garrone B, Srinivasa P, Crane DI, Lavin MF. Localization of a portion of extranuclear ATM to peroxisomes J Biol Chem 1999 Nov 26;274(48):34277-82

Tripathi DN, Walker CL. The peroxisome as a cell signaling organelle Curr Opin Cell Biol 2016 Apr;39:109-12

Zhang J, Tripathi DN, Jing J, Alexander A, Kim J, Powell RT, Dere R, Tait-Mulder J, Lee JH, Paull TT, Pandita RK,

Charaka VK, Pandita TK, Kastan MB, Walker CL. ATM functions at the peroxisome to induce pexophagy in response to ROS Nat Cell Biol 2015 Oct;17(10):1259-69

Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, Cleveland JL, Green DR, Kastan MB. Mitochondrial dysfunction in ataxia-telangiectasia Blood 2012 Feb 9;119(6):1490-500

Rotman G, Shiloh Y. Ataxia-telangiectasia: is ATM a sensor of oxidative damage and stress? Bioessays 1997 Oct;19(10):911-7 Review

Rotman G, Shiloh Y. The ATM gene and protein: possible roles in genome surveillance, checkpoint controls and cellular defence against oxidative stress Cancer Surv 1997;29:285-304

Barzilai A, Rotman G, Shiloh Y. ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage DNA Repair (Amst) 2002 Jan 22;1(1):3-25

Watters DJ. Oxidative stress in ataxia telangiectasia Redox Rep 2003;8(1):23-9

Takao N, Li Y, Yamamoto K. Protective roles for ATM in cellular response to oxidative stress FEBS Lett 2000 Apr 21;472(1):133-6

Alexander A, Cai SL, Kim J, Nanez A, Sahin M, MacLean KH, Inoki K, Guan KL, Shen J, Person MD, Kusewitt D, Mills GB, Kastan MB, Walker CL. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS Proc Natl Acad Sci U S A 2010 Mar 2;107(9):4153-8

Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT. ATM activation by oxidative stress Science 2010 Oct 22;330(6003):517-21

Guo Z, Deshpande R, Paull TT. ATM activation in the presence of oxidative stress Cell Cycle 2010 Dec 15;9(24):4805-11

Lee JH, Guo Z, Myler LR, Zheng S, Paull TT. Direct activation of ATM by resveratrol under oxidizing conditions PLoS One 2014 Jun 16;9(6):e97969

Semlitsch M, Shackelford RE, Zirkl S, Sattler W, Malle E. ATM protects against oxidative stress induced by oxidized low-density lipoprotein DNA Repair (Amst) 2011 Aug 15;10(8):848-60

Kr+ACY-uuml;ger A, Ralser M. ATM is a redox sensor linking genome stability and carbon metabolism Sci Signal 2011 Apr 5;4(167):pe17

Kozlov SV, Waardenberg AJ, Engholm-Keller K, Arthur JW, Graham ME, Lavin M. Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen Mol Cell Proteomics 2016 Mar;15(3):1032-47

Tripathi DN, Chowdhury R, Trudel LJ, Tee AR, Slack RS, Walker CL, Wogan GN. Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2-mediated suppression of mTORC1 Proc Natl Acad Sci U S A 2013 Aug 6;110(32):E2950-7

Zhang J, Kim J, Alexander A, Cai S, et al. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS Nat Cell Biol 2013 Oct;15(10):1186-96

Alexander A, Kim J, Walker CL. ATM engages the TSC2/mTORC1 signaling node to regulate autophagy Autophagy 2010 Jul;6(5):672-3

Alexander A, Walker CL. Differential localization of ATM is correlated with activation of distinct downstream signaling pathways Cell Cycle 2010 Sep 15;9(18):3685-6

Till A, Lakhani R, Burnett SF, Subramani S. Pexophagy: the selective degradation of peroxisomes Int J Cell Biol 2012;2012:512721

Ambrose M, Goldstine JV, Gatti RA. Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells Hum Mol Genet 2007 Sep 15;16(18):2154-64

Eaton JS, Lin ZP, Sartorelli AC, Bonawitz ND, Shadel GS. Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis J Clin Invest 2007 Sep;117(9):2723-34

Fu X, Wan S, Lyu YL, Liu LF, Qi H. Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation PLoS One 2008 Apr 23;3(4):e2009

Valentin-Vega YA, Kastan MB. A new role for ATM: regulating mitochondrial function and mitophagy Autophagy 2012 May 1;8(5):840-1

D'Souza AD, Parish IA, Krause DS, Kaech SM, Shadel GS. Reducing mitochondrial ROS improves disease-related



pathology in a mouse model of ataxia-telangiectasia Mol Ther 2013 Jan;21(1):42-8

Sharma NK, Lebedeva M, Thomas T, Kovalenko OA, Stumpf JD, Shadel GS, Santos JH. Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia DNA Repair (Amst) 2014 Jan;13:22-31

Chen H, Ruiz PD, McKimpson WM, Novikov L, Kitsis RN, Gamble MJ. MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype Mol Cell 2015 Sep 3;59(5):719-31

Kang C, Xu Q, Martin TD, Li MZ, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4 Science 2015 Sep 25;349(6255):aaa5612

Aird KM, Worth AJ, Snyder NW, Lee JV, Sivanand S, Liu Q, Blair IA, Wellen KE, Zhang R. ATM couples replication stress and metabolic reprogramming during cellular senescence Cell Rep 2015 May 12;11(6):893-901

Cosentino C, Grieco D, Costanzo V. ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair EMBO J 2011 Feb 2;30(3):546-55

Yang DQ, Kastan MB. Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1 Nat Cell Biol 2000 Dec;2(12):893-8

Miles PD, Treuner K, Latronica M, Olefsky JM, Barlow C. Impaired insulin secretion in a mouse model of ataxia telangiectasia Am J Physiol Endocrinol Metab 2007 Jul;293(1):E70-4

Viniegra JG, Mart+ACY-iacute;nez N, et al. Full activation of PKB/Akt in response to insulin or ionizing radiation is mediated through ATM J Biol Chem 2005 Feb 11;280(6):4029-36

Halaby MJ, Hibma JC, He J, Yang DQ. ATM protein kinase mediates full activation of Akt and regulates glucose transporter 4 translocation by insulin in muscle cells Cell Signal 2008 Aug;20(8):1555-63

Jeong I, Patel AY, Zhang Z, Patil PB, et al. Role of ataxia telangiectasia mutated in insulin signalling of muscle-derived cell lines and mouse soleus Acta Physiol (Oxf) 2010 Apr;198(4):465-75

Wu D, Yang H, Xiang W, Zhou L, Shi M, Julies G, Laplante JM, Ballard BR, Guo Z. Heterozygous mutation of ataxia-telangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice J Lipid Res 2005 Jul;46(7):1380-7

Schneider JG, Finck BN, Ren J, et al. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome Cell Metab 2006 Nov;4(5):377-89

Mercer JR, Cheng KK, Figg N, Gorenne I, et al. DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome Circ Res 2010 Oct 15;107(8):1021-31

Mercer JR, Yu E, Figg N, Cheng KK, et al. The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM/ApoE-/- mice Free Radic Biol Med 2012 Mar 1;52(5):841-9

Peretz S, Jensen R, Baserga R, Glazer PM. ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response Proc Natl Acad Sci U S A 2001 Feb 13;98(4):1676-81

Goetz EM, Shankar B, Zou Y, et al. ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability Oncogene 2011 Sep 1;30(35):3745-54

Ching JK, Luebbert SH, Collins RL 4th, Zhang Z, Marupudi N, Banerjee S, Hurd RD, Ralston L, Fisher JS. Ataxia telangiectasia mutated impacts insulin-like growth factor 1 signalling in skeletal muscle Exp Physiol 2013 Feb;98(2):526-35

Luo X, Suzuki M, Ghandhi SA, Amundson SA, Boothman DA. ATM regulates insulin-like growth factor 1-secretory clusterin (IGF-1-sCLU) expression that protects cells against senescence PLoS One 2014 Jun 17;9(6):e99983

Foster CR, Singh M, Subramanian V, Singh K. Ataxia telangiectasia mutated kinase plays a protective role in +ACY-beta;-adrenergic receptor-stimulated cardiac myocyte apoptosis and myocardial remodeling Mol Cell Biochem 2011 Jul;353(1-2):13-22

Foster CR, Zha Q, Daniel LL, Singh M, Singh K. Lack of ataxia telangiectasia mutated kinase induces structural and functional changes in the heart: role in +ACY-beta;-adrenergic receptor-stimulated apoptosis Exp Physiol 2012 Apr;97(4):506-15

Foster CR, Daniel LL, Daniels CR, Dalal S, Singh M, Singh K. Deficiency of ataxia telangiectasia mutated kinase modulates cardiac remodeling following myocardial infarction: involvement in fibrosis and apoptosis PLoS One 2013 Dec 16;8(12):e83513

Daniel LL, Daniels CR, Harirforoosh S, Foster CR, Singh M, Singh K. Deficiency of ataxia telangiectasia mutated kinase delays inflammatory response in the heart following myocardial infarction J Am Heart Assoc 2014 Dec;3(6):e001286

Swift M, Chase C. Cancer and cardiac deaths in obligatory ataxia-telangiectasia heterozygotes Lancet 1983 May 7;1(8332):1049-50

Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles Ann Intern Med 2000 Nov 21;133(10):770-8

This article should be referenced as such:

Shiloh Y. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):237-248.

Leukaemia Section Short Communication




del (5q) solely in Myelodysplastic syndrome Nahid Shahmarvand, Robert S. Ohgami

Department of Pathology, Stanford University, Stanford, CA, USA;

[email protected]

Published in Atlas Database: October 2016

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del5qSoleID1134.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68261/10-2016-del5qSoleID1134.pdf DOI: 10.4267/2042/68261


Abstract Review on Myelodysplastic syndrome with isolated

deletion of 5q

Keywords

Myelodysplastic syndrome; chromosome 5; deletion

5q

Identity

del (5q) solely in Myelodysplastic syndrome

Other names

Myelodysplastic syndrome with isolated deletion of

5q

Clinics and pathology

Disease

Myelodysplastic syndrome (MDS) with isolated

deletion of chromosome 5q is part of a group of

clonal disorders in myeloid stem cells with

ineffective hematopoiesis which is manifested by

morphologic dysplasia in hematopoietic cells and

single or bilineage cytopenia(s). It is the only MDS

subtype defined cytogenetically in the World Health

Organization classification system.

Phenotype/cell stem origin

Myeloid stem cell.

Epidemiology

MDS with isolated del(5q) is present in <5% of MDS

cases (Mallo et al., 2011). It occurs more often in

women than in men, male:female ratio 7:3,

with a median age of diagnosis at 65 to 70 years.

Clinics

Patients suffering from MDS with isolated del(5q)

present with a macrocytic anemia, normal or

increased platelet count and absence of significant

neutropenia in their peripheral blood. The incidence

of bleeding and infections is therefore low in these

patients because of the absence of significant

neutropenia and thrombocytopenia. Blood

transfusion dependency is seen in patients with

severe anemia at diagnosis but also can develop in

other patients (Germing et al., 2012). According to

the Revised International Prognostic Scoring System

(IPSS-R), MDS with isolated del(5q) are defined as

Low- or Intermediate -1- risk subtypes and usually

have an indolent course.

Pathology

The bone marrow is characterized by an increase in

the number of small megakaryocytes with

monolobulated and bilobulated nuclei. There are less

than 1% blasts in the peripheral blood and less than

5% blasts in the bone marrow and Auer Rods are

absent (Arber et al., 2016).

Treatment

MDS patients with isolated del(5q) have a favorable

prognosis and the majority of patients respond well

to treatment with lenalidomide.

Prognosis

This subtype of MDS has a favorable prognosis. The

exception is when this disease is associated with

mutations in TP53.

http://documents.irevues.inist.fr/bitstream/DOI%20del5qSoleID1134.txt

del (5q) solely in Myelodysplastic syndrome Shahmarvand N, Ohgami RS


Figure 1: An example of a typical hypolobated micromegakaryocyte in a bone marrow aspirate smear. (Wright-Giemsa)

Cytogenetics

Cytogenetics morphological

As its name implies, in this entity there is interstitial

deletion of part of the long arm of chromosome 5

involving 5q31-5q33. MDS with isolated del(5q) can

still be diagnosed if there is 1 additional cytogenetic

abnormality besides del(5q) if there is no adverse

effect of that abnormality, as such, this excludes

{CC: TXT:monosomy 7 or del 7(q) ID:} for instance

(Arber et al., 2016).

Cytogenetics molecular

The gene specific for the defect seen in MDS with

isolated del(5q) has been identified by RNA

interference screening to be RPS14 (Pellagatti et al.,

2008).

In addition, while patients with MDS with isolated

del(5q) classically have a favorable prognosis, the

presence of a TP53 mutation is of particular

importance, this mutation predicts for poorer

prognosis and higher risk of transformation to AML

(Mallo et al.,2013).

Figure 2: The karyotype in a case of MDS with isolated del(5q) showing 46,XX,del(5)(q22q35). Image courtesy of Dana Bangs, CG(ASCP), Stanford University.

del (5q) solely in Myelodysplastic syndrome Shahmarvand N, Ohgami RS


Genes involved and proteins

RPS14 (ribosomal protein S14)

Location

5q33.1

Protein

RPS14 is a ribosomal gene located in commonly

deleted region (CDR) of 5q. It encodes for a protein

required for maturation of 40S ribosomal subunits.

Patients with MDS with del(5q) are haploinsufficient

for RPS14 which leads to impairment of ribosome

biogenesis and subsequent reduction of protein

translation.

TP53 (Tumour protein p53 (Li-Fraumeni syndrome))

Location

17p13.1

Protein

The TP53 gene encodes for the tumor suppressor

protein p53. In the presence of DNA -damage p53

may be activated to fix the damage, or if the damage

cannot be repaired p53 prevents the cell from

dividing and signals the cell to undergo apoptosis.

References Arber DA, Hasserjian RP. Reclassifying myelodysplastic syndromes: what's where in the new WHO and why. Hematology Am Soc Hematol Educ Program. 2015;2015:294-8

Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405

Bejar R. Clinical and genetic predictors of prognosis in myelodysplastic syndromes. Haematologica. 2014 Jun;99(6):956-64

Germing U, Lauseker M, Hildebrandt B, Symeonidis A, Cermak J, Fenaux P, Kelaidi C, Pfeilstöcker M, Nösslinger T, Sekeres M, Maciejewski J, Haase D, Schanz J, Seymour J, Kenealy M, Weide R, Lübbert M, Platzbecker U, Valent P, Götze K, Stauder R, Blum S, Kreuzer KA,

Schlenk R, Ganser A, Hofmann WK, Aul C, Krieger O, Kündgen A, Haas R, Hasford J, Giagounidis A. Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): a multicenter study. Leukemia. 2012 Jun;26(6):1286-92

Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G, Hedlund A, Hast R, Schlegelberger B, Porwit A, Hellström-Lindberg E, Mufti GJ. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. 2011 May 20;29(15):1971-9

Mallo M, Cervera J, Schanz J, Such E, García-Manero G, Luño E, Steidl C, Espinet B, Vallespí T, Germing U, Blum S, Ohyashiki K, Grau J, Pfeilstöcker M, Hernández JM, Noesslinger T, Giagounidis A, Aul C, Calasanz MJ, Martín ML, Valent P, Collado R, Haferlach C, Fonatsch C, Lübbert M, Stauder R, Hildebrandt B, Krieger O, Pedro C, Arenillas L, Sanz MÁ, Valencia A, Florensa L, Sanz GF, Haase D, Solé F. Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q. Leukemia. 2011 Jan;25(1):110-20

Mallo M, Del Rey M, Ibáñez M, Calasanz MJ, Arenillas L, Larráyoz MJ, Pedro C, Jerez A, Maciejewski J, Costa D, Nomdedeu M, Diez-Campelo M, Lumbreras E, González-Martínez T, Marugán I, Such E, Cervera J, Cigudosa JC, Alvarez S, Florensa L, Hernández JM, Solé F. Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of cytogenetics and mutations. Br J Haematol. 2013 Jul;162(1):74-86

Patnaik MM, Lasho TL, Finke CM, Knudson RA, Ketterling RP, Chen D, Hoyer JD, Hanson CA, Tefferi A. Isolated del(5q) in myeloid malignancies: clinicopathologic and molecular features in 143 consecutive patients. Am J Hematol. 2011 May;86(5):393-8

Pellagatti A, Hellström-Lindberg E, Giagounidis A, Perry J, Malcovati L, Della Porta MG, Jädersten M, Killick S, Fidler C, Cazzola M, Wainscoat JS, Boultwood J. Haploinsufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes. Br J Haematol. 2008 Jul;142(1):57-64

Saft L, Karimi M, Ghaderi M, Matolcsy A, Mufti GJ, Kulasekararaj A, Göhring G, Giagounidis A, Selleslag D, Muus P, Sanz G, Mittelman M, Bowen D, Porwit A, Fu T, Backstrom J, Fenaux P, MacBeth KJ, Hellström-Lindberg E. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q). Haematologica. 2014 Jun;99(6):1041-9


Shahmarvand N, Ohgami RS. del (5q) solely in Myelodysplastic syndrome. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):249-251.





del(9p) in Acute Lymphoblastic Leukemia Anwar N. Mohamed

Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University

School of Medicine, Detroit, MI USA. [email protected]

Published in Atlas Database: September 2016

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del9pALLID1064.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68262/09-2016-del9pALLID1064.pdf DOI: 10.4267/2042/68262


Abstract Review on del(9p) in acute lymphoblastic leukemia,

with data on clinics, and the genes involved.

Keywords

chromosome 9; del(9p); acute lymphoblastic

leukemia

Identity

Deletion of 9p is a common recurring chromosomal

aberration in acute lymphoblastic leukemia (ALL) of

both B- and T-lineages ALL. The 9p region contains

numerous cancer-associated genes such as JAK2,

CD274 (PDL1)/ PDCD1LG2 (PDL2) at 9p24.1,

CDKN2A, CDKN2B, MTAP, IFN, MLLT3, and

HACD4 (PTPLAD2) at 9p21.3 as well as PAX5 at

9p13.2. Several of these genes have been implicated

in the leukemogenesis of ALL (Mullighan CG 2012,

Harrison CJ 2013).


Disease

Acute lymphoblastic leukemia (ALL)

Epidemiology

Visible deletions of 9p by karyotype are seen in

approximately 10% of ALL cases of both children

(7-11%) and adult (5-15%). The loss of 9p is the

second most frequent abnormality after t(9;22)/Ph in

adult ALL, and the third after high

hyperdiploidy and t(12;21) inpediatric ALL

(Moorman et al 2010). The minimal commonly

deleted segment is band 9p21 encompassing the

tumor suppressor genes CDKN2A and CDKN2B.

Clinics

At diagnosis patients are likely to have higher WBC

counts, older age, male gender, splenomegaly, and

hypodiploid karyotype than patients lacking 9p

deletions (Heerema et al 1999). In addition, patients

with a 9p abnormality have an increasing incidence

of both marrow and central nervous system relapses.

Prognosis

The prognostic significance of 9p21/CDKN2A

deletion has remained indecisive particularly in

pediatric B-ALL. The differences in patient

population and study designs among different

studies may have had an impact on the overall

results.

In Pediatric B-ALL Initial studies on a small

number of patients suggested that deletion of

9p/CDKN2A was associated with an increased risk

of relapse and death although other report concluded

no prognostic effect on the disease outcome (Kees et

al 1997, Zhou et al 1997). On a large cohort study,

Heerema et al showed a high frequency of 9p

abnormalities in ALL patients with high-risk or

lymphomatous features, and an overall poorer

outcome compared with those lacking this

abnormality. Their data also indicated that 9p

abnormalities identify a subgroup of NCI standard-

risk patients with increased risk of treatment failure.

del(9p) in Acute Lymphoblastic Leukemia Mohamed AN


Figure 1; Top: Partial G-banded karyotype showing partial deletion 9p, der(9;16)(q10;p10), i(9(q10) [left to right]. Bottom: FISH on metaphase cell (left) and interphase cell (right) showing one copy of CDKN2A (orange signal) and two copies of CEP 9 (green

signal)

Yet, the recent study by Sulong et al concluded that

CDKN2A deletion is a significant secondary genetic

abnormality and variation in the incidence of

CDKN2A deletion among the cytogenetic subgroups

may explain its inconsistent association with

outcome.

Conversely, the dicentric (9;12) has been associated

with a favorable outcome in pediatric ALL.

In Adult B-ALL Patients with 9p deletions have

significantly shorter overall survival when compared

with patients with normal karyotypes. The overall

survival is similar to that in the poor prognosis t(9;22

)/ BCR/ ABL1-positive group (Nahi et al 2008).

In T-ALL The prognostic implications of loss of

heterozygosity (LOH) of 9p were evaluated in

pediatric T-ALL patients treated uniformly

according to the Berlin-Frankfurt-Munster regimen.

This study showed that LOH of 9p was associated

with a favorable initial treatment response, and the

event free survival was slightly favorable (Krieger et

al 2010).

Cytogenetics

Cytogenetics morphological The loss of material from 9p can result from a simple

deletion in approximately 40% of cases or from

various unbalanced translocations giving rise to a

partial or complete loss of 9p such as isochromsome

i(9)(q10), dicentric dic(9;12) and dic(9;20), whole

arm der(V;9q10), and add(9p) [Figure 1].

The majority of 9p deletions are associated with a

nonhyperdiploid karyotype (Heerema et al 1999).

Although deletion of 9p occurs as a sole abnormality

in ~20% of cases, it is frequently accompanied by

other primary genetic abnormalities such as

t(1;19)(q23;p13.3), t(9;22)(q34;q11.2),

t(12;21)(p13;q22), t(14q32) and inv(14)(q11.2q32)

suggesting that 9p deletion is a secondary change.

Deletions of 9p often are not easily detected by G-

banding.

Therefore, FISH testing targeting the CDKN2A gene

provides an excellent method for detecting the

majority of these deletions.

In large series studies, the frequency of CDKN2A/B

deletions has been reported in 20%-34% of B- ALL

but is significantly higher among T-ALL patients

50%-80%.

The distribution of 9p deletion among the

cytogenetic subgroups varies. Patients with t(9;22)

and t(1;19) have higher incidences of CDKN2A/B

deletion (40%-60%) than patients with high

hyperdiploidy, ETV6/ RUNX1 fusion , or KMT2A

(MLL)/11q23 rearrangements (11%-15%).

Both monoallelic and biallelic CDKN2A deletions

are found in ALL with the latter being more

prevalent in T-ALL (Sulong et al, 2009).

The deletions vary in size considerably from <1 Mb

to 39 Mb, and the biallelic deletions consist of a large

and small deletion. In contrast, inactivation of

CDKN2A gene in ALL by mutation or

hypermethylation appears to be low, ranging from 0-

7%.




CDKN2A (cyclin dependent kinase 2a / p16)

Location

9p21.3

Note

CDKN2A (Cyclin Dependent Kinase Inhibitor 2A),

alternative symbols included CDKN2, CDK4

inhibitor, multiple tumor suppressor 1(MTS1),

TP16, p16(INK4), p16(INK4A)

DNA/RNA

CDKN2A consists of three coding exons spanning

over 30kb.

Protein

CDKN2A gene encodes two major proteins

p16(INK4) and p14(ARF) through the use of shared

coding regions and alternative reading frames. Both

act as tumor suppressors by regulating the cell cycle.

The p16 prevents progression through the G1 cell

cycle checkpoint by inhibiting cyclin-dependent

kinases CDK4 and CDK6 to inactivate the

retinoblastoma ( RB1) family of tumor suppressor

proteins.

The p14 protein acts primarily by deterring MDM2

and therefore, promotes p53 protein, consequently

inducing cell cycle arrest in both G1 and G2/M

phases as well as initiating apoptosis.

Somatic mutations

Somatic mutations of CDKN2A are common in

human cancers, with estimates that CDKN2A is the

second most commonly inactivated gene in cancer

after TP53.

Germline mutations of CDKN2A are associated with

familialmelanoma, glioblastoma and pancreatic

cancer.

CDKN2B (cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4))

Location

9p21.3

Note

CDKN2B (Cyclin-Dependent Kinase Inhibitor 2B),

alternative symbols included; Multiple Tumor

Suppressor 2 (MTS2), p15(INK4B), TP15,

CDKN4B inhibitor.

Protein

CDKN2B encodes a cyclin-dependent kinase

inhibitor "p15", which forms a complex with CDK4

or CDK6, and prevents the activation of the CDK

kinases.

The p15 protein functions as a cell growth regulator

that controls cell cycle G1 progression.

Somatic mutations

CDKN2B is tandemly linked to CDKN2A and

frequently deleted in a significant proportion of

ALL, but always in association with CDKN2A.

PAX5 (paired box gene 5)

Location

9p13.2

Note

PAX5 (Paired Box Gene 5), alternative symbols

ALL3, BSAP

Protein

PAX5 gene encodes a B-cell-specific activator

protein (BSAP), which is a member of a class of

transcription factors that contains a DNA-binding

domain. It is the only member of PAX family

expressed in the hematopoietic system exclusively in

B-cells. Expression of PAX5 is initiated in pre-pro-

B cells and maintained throughout subsequent stages

of B-cell development before it is down-regulated in

plasma cell. It functions both as a transcriptional

activator and as a repressor on different target genes,

which are involved in B-lineage development.

Germinal mutations

Recently germline mutation of PAX5 gene was

identified by exome sequencing in two unrelated

families. The affected family members had B-cell

precursor ALL and the diagnostic and relapse

leukemic samples from both families demonstrated

deletion of 9p through i(9)(q10) or dicentric (9q;v),

both of which resulted in loss of the wild-type PAX5

allele and retention of mutated PAX5. The loss

resulted in a marked reduction of normal PAX5

activity in the leukemia cells.

Somatic mutations

Somatic alterations of PAX5 gene due to deletions,

point mutations, or translocations occur in

approximately 30% of B-ALL and in up to 50% of

the high-risk BCR-ABL1 positive and Ph-like ALL

subtypes. Alterations of PAX5 are not associated

with an adverse outcome in children or adult B-cell

ALL (Mullighan et al 2012, Shahjahani et al 2015).

JAK2 (janus kinase 2)

Location

9p24.1

Note

JAK2 (Janus kinase 2 gene), alternative symbol

JTK10.

Protein

JAK2 encodes a non-receptor tyrosine kinase that is

involved in a specific subset of cytokine receptor

signaling pathways. It has been found to be

constitutively associated with the prolactin receptor

(PRLR) and is required for responses to gamma

interferon ( IFNG). Upon receptor activation JAK2

phosphorylate the transcription factors "STATs" and

initiate the JAK-STAT signaling pathway.

Somatic mutations

Mutations of JAK1/2 have been identified in 18%-

35% Down syndrome - ALL and also occur in about



10% of high-risk pediatric B- ALL patients causing

a constitutive activation of the JAK-STAT pathway.

The most frequent site of mutation is at R683 in the

pseudokinase domain of JAK2 which is distinct from

the JAK2 V617F predominant mutation seen in

polycythemia vera and other myeloproliferative

neoplasms (Robert et al 2012, Hunger and Mullighan

2015). The presence of JAK mutations is

significantly associated with alteration of IKZF1 and

rearrangement of CRLF2 signifying a high risk

disease and poor outcome. ALL cases harboring

CRLF2 and JAK alterations may benefit from JAK

inhibitors targeted therapy.

References Harrison CJ. Targeting signaling pathways in acute lymphoblastic leukemia: new insights. Hematology Am Soc Hematol Educ Program. 2013;2013:118-25

Heerema NA, Sather HN, Sensel MG, Liu-Mares W, Lange BJ, Bostrom BC, Nachman JB, Steinherz PG, Hutchinson R, Gaynon PS, Arthur DC, Uckun FM. Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: A report from the Children's Cancer Group. Blood. 1999 Sep 1;94(5):1537-44

Hunger SP, Mullighan CG. Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine. Blood. 2015 Jun 25;125(26):3977-87

Kees UR, Burton PR, Lü C, Baker DL. Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome. Blood. 1997 Jun 1;89(11):4161-6

Krieger D, Moericke A, Oschlies I, Zimmermann M, Schrappe M, Reiter A, Burkhardt B. Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia. Haematologica. 2010 Jan;95(1):158-62

Moorman AV, Ensor HM, Richards SM, Chilton L, Schwab C, Kinsey SE, Vora A, Mitchell CD, Harrison CJ. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol. 2010 May;11(5):429-38

Mullighan CG. The molecular genetic makeup of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2012;2012:389-96

Nahi H, Hägglund H, Ahlgren T, Bernell P, Hardling M, Karlsson K, Lazarevic VLj, Linderholm M, Smedmyr B, Aström M, Hallböök H. An investigation into whether deletions in 9p reflect prognosis in adult precursor B-cell acute lymphoblastic leukemia: a multi-center study of 381 patients. Haematologica. 2008 Nov;93(11):1734-8

Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, Chen SC, Payne-Turner D, Churchman ML, Harvey RC, Chen X, Kasap C, Yan C, Becksfort J, Finney RP, Teachey DT, Maude SL, Tse K, Moore R, Jones S, Mungall K, Birol I, Edmonson MN, Hu Y, Buetow KE, Chen IM, Carroll WL, Wei L, Ma J, Kleppe M, Levine RL, Garcia-Manero G, Larsen E, Shah NP, Devidas M, Reaman G, Smith M, Paugh SW, Evans WE, Grupp SA, Jeha S, Pui CH, Gerhard DS, Downing JR, Willman CL, Loh M, Hunger SP, Marra MA, Mullighan CG. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012 Aug 14;22(2):153-66

Shahjahani M, Norozi F, Ahmadzadeh A, Shahrabi S, Tavakoli F, Asnafi AA, Saki N. The role of Pax5 in leukemia: diagnosis and prognosis significance. Med Oncol. 2015 Jan;32(1):360

Sulong S, Moorman AV, Irving JA, Strefford JC, Konn ZJ, Case MC, Minto L, Barber KE, Parker H, Wright SL, Stewart AR, Bailey S, Bown NP, Hall AG, Harrison CJ. A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups. Blood. 2009 Jan 1;113(1):100-7

Zhou M, Gu L, Yeager AM, Findley HW. Incidence and clinical significance of CDKN2/MTS1/P16ink4A and MTS2/P15ink4B gene deletions in childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1997 Mar-Apr;14(2):141-50


Mohamed AN. del(9p) in Acute Lymphoblastic Leukemia. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):252-255.





der(X)t(X;8)(q28;q11.2) Tatiana Gindina

R.M. Gorbacheva Research Institute of Pediatric Oncology Hematology and Transplantation at First

Saint-Petersburg State Medical University named I.P.Pavlov, Saint-Petersburg, Russia /

[email protected]


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0X08q28q11ID1641.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68263/09-2016-t0X08q28q11ID1641.pdf DOI: 10.4267/2042/68263


Abstract Review on der(X)t(X;8)(q28;q11.2), with data on

clinics

Keywords

chromosome X; chromosome 8;

der(X)t(X;8)(q28;q11.2); acute lymphoblastic

leukemia

Identity

Partial GTG-banding karyotype of the der(X)t(X;8)(q28;q11.2).


Disease

Acute lymphoblastic leukemia


Leukemic cells were positive for CD34, CD10,

CD19, CD20, CD38.

Epidemiology

Extremely rare karyotypic event in ALL; both ALL

patients were males (aged 4 and 19 years).

Clinics

Among the characteristic laboratory features were a

low WBC at presentation. One of the two ALL

patients had a few reddish skin nodules 5-7 mm in

diameter, moderate hepatosplenomegaly. No patient

had a mediastinal mass or central nervous system

involvement at diagnosis, but one patient had CNS

extramedullary relapses, including post-transplant.

Case Leukemia Age/

Sex

WBC

109/L Karyotype Outcome References

1

B-

precursor

ALL

4/M 20 46,Y,der(X)t(X;8)(q28;q11.2),t(9;22)(q34;q11)

,t(8;14)(q11.2;q32),add(17)(p13)

CR; Relapsed after 23,5

mths

Kaleem et

al., 2000

2 Common

B ALL 19/M 17 46,Y,der(X)t(X;8)(q28;q11.2)

CR; Complex medullar and

CNS extramedullary

relapses after 10 mths and

13 mths; CR after BMT;

Isolated post-transplant

CNS relapse; died after 29

mths after diagnosis

Present

case, 2016

der(X)t(X;8)(q28;q11.2) Gindina T


Micro- and macrogenerations of lymphoblasts. Blasts had rounded nucleus and finely dispersed chromatin with well-contoured nucleoli. Iconography courtesy Valentina Kravtsova.

Cytology

Bone marrow are hypercellular with 54.4%

lymphoblasts of L1 or L2 morphology.

They were negative for myeloperoxidase, whereas

most of them positive for PAS stain. Erythropoiesis

and myelopoiesis were decreased. Erythropoiesis

had signs of megaloblastosis.

Megakaryocytopoiesis: hypolobular and polyploid

megakaryocytes.

Pathology

Histopathology of the skin nodules was remarkable

for interstitially located groups of small- and middle-

sized lymphoid blast-like cells, which were positive

for TdT, PAX-5, CD20, CD10, negative for T-cell

and myeloid markers and had a very high

proliferation rate (Ki-67 index above 90 %). myc

oncogene product was additionally assessed with

immunohistochemistry (clone Y69). Over 90% of

blast cells in the skin appeared to be positive for myc,

although staining pattern was markedly

heterogeneous. The brain tissue (at post-transplant

relapse) contained a dense cellular infiltrate

composed of middle-sized PAS-positive blasts with

oval or round nuclei, containing 2-3 small nucleoli.

Tumor cells were uniformly positive for TdT, CD19,

PAX-5, and CD79a and had a very high Ki-67

proliferation index. myc oncogene product was

demonstrated in over 85% of cells with

heterogeneous staining pattern, compatible with

indirect myc up-regulation.

Treatment

Complete therapeutic data are available for one of

the two ALL cases: treatment was started according

to ALL-2009 protocol, containing Daunorubicin,

Vincristine, and L-asparaginase. CNS prophylaxis

therapy consisted of triple intrathecal treatments,

whereas cranial irradiation was not used. The patient

received allogeneic HSCT; conditioning regimen

consisted of Melphalan and Fludarabine.

Prognosis

The risk associated with der(X)t(X;8)(q28;q11.2) is

not well determined due to low number of cases.

Cytogenetics


Isolated derivative chromosome X was

demonstrated in one ALL case (present case, 2016);

in second one, the derivative chromosome X was

combined with other recurrent chromosomal

abnormalities (Kaleem et al, 2000).

Probes

Whole chromosome painting (WCP X, WCP8),

mBAND 8 (Metasystems, Germany).

Additional anomalies

Found in association with t(9;22)(q34;q11),

t(8;14)(q11.2;q32) and add(17)(p13) in one ALL

case (Kaleem et al,2000).

der(X)t(X;8)(q28;q11.2) Gindina T


GTG-banding showing the derivative X chromosome; FISH with whole painting probes showing two normal chromosomes 8 (green color) and the derivative der(X)t(X;8) (red and green colors). Multicolor banding of two normal chromosomes 8 and the

derivative X chromosome.


The unbalanced translocation

der(X)t(X;8)(q28;q11.2) results in a partial 8q

trisomy.

Result of the chromosomal anomaly

Hybrid gene

No specific gene or protein are described.

Fusion protein

Oncogenesis

The presence of partial 8q trisomy leads to gain of

genetic material and consequently to amplification

of genes possibly involved in the neoplastic process.

MYC is one of the genes located on 8q which may

be implicated in disease biology.

Immunohistochemical staining for MYC protein

showed positivity of >85% of leukemic cells,

although with markedly heterogeneous staining

pattern, compatible with indirect MYC up-

regulation. The latter, in turn, could increase

proliferative potential of leukemic cells as well as

their resistance to chemotherapy. In several studies,

trisomy 8 in ALL patients is considered to be

indicative of poor prognosis (Garipidou et al).

References Garipidou V, Yamada T, Prentice HG, Secker-Walker LM. Trisomy 8 in acute lymphoblastic leukemia (ALL): a case report and update of the literature. Leukemia. 1990 Oct;4(10):717-9

Kaleem Z, Shuster JJ, Carroll AJ, Borowitz MJ, Pullen DJ, Camitta BM, Zutter MM, Watson MS. Acute lymphoblastic leukemia with an unusual t(8;14)(q11.2;q32): a Pediatric Oncology Group Study. Leukemia. 2000 Feb;14(2):238-40


Gindina T. der(X)t(X;8)(q28;q11.2). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):256-258.





t(1;9)(q24;q34) RCSD1/ABL1 Adriana Zamecnikova, Soad al Bahar

Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait;

[email protected]


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0109q24q34ID2109.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68264/09-2016-t0109q24q34ID2109.pdf DOI: 10.4267/2042/68264

This article is an update of : De Braekeleer E, De Braekeleer M. t(1;9)(q24;q34). Atlas Genet Cytogenet Oncol Haematol 2008;12(6)


Abstract Review on t(1;9)(q24;q34) translocation, with data

on clinics, and the genes involved.

Keywords

chromosome 1; chromosome 9; ABL1; RCSD1; B-

cell acute lymphoblastic leukemia

Clinics and pathology Disease

B-cell precursor ALL with expression of CD79a+,

CD19+, CD10+, TdT (Mustjoki et al., 2009; Collette

et al., 2015 )

Epidemiology

12 cases with an ABL1 split by FISH and/or

RCSD1/ABL1 fusion, aged 5 to 40 years (median

age 15 years); male predominance (8 males and 4

females); among them 1 with ABL1-positive

biphenotypic ALL in which, however, the partner

gene has not been identifed.

Cytology

Hyperleukocytosis (WBC range at diagnosis 24 to

470 x 109, median 110 x 109); bone marrow blasts

ranging from 58 to 95%.

Prognosis Poor response to induction chemotherapy and in

addition to induction failure, a high risk of relapse

including patients after bone marrow transplantation.

B-ALL patients with the RCSD1/ABL1 fusion are

characterized by susceptibility to tyrosine kinase

inhibitor therapy

(imatinib, dasatinib, ponatinib) and may achieve

transient clinical effects as well as long time

remission (Table 1; Data from De Braekeleer et al.,

2013; Perwein et al., 2016) )

Cytogenetics

See Figure 1.


ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)

Location

9q34.12

DNA/RNA

The ABL gene is aproximately 225 kb in size and is

expressed as a 7-kb mRNA transcript, with

alternatively spliced first exons, exons 1b and 1a,

respectively, spliced to the common exons 2-11.

Exon 1b is approximately 200 kb 5-prime of exon

1a.

Protein

The 145-kD ABL protein is classified as a

nonreceptor tyrosine kinase.

When the N-terminal region of the ABL protein is

encoded by exon 1a, the protein is believed to be

localized in the nucleus, while when encoded by

exon 1b, the resulting N-terminal glycine would be

myristylated and thus postulated to direct that

protein to the plasma membrane.

t(1;9)(q24;q34) RCSD1/ABL1 Zamecnikova A, al Bahar S


Sex/

Age Diagnosis

WBC

(x109/L)

PB/BM

blasts

(%)

Genetic testing results Therapy Survival

(months)

1 M/15 BAL 122 95/ NA 46,XY,t(1;9)(q23.3~q25;q34)

ABL1-rearranged (FISH) Chemotherapy 10 died

2* M/11 B-ALL 6 47/92

46,Y,add(X)(p22),t(1;9)(q24;q34)

ABL1-rearranged (FISH)

RCSD1-ABL1

Chemotherapy, BMT,

relapsed 2 years after

the initial treatment

97

3 40/M B-ALL 24 34/80 46,XY,t(1;9)(q24;q34)

RCSD1-ABL1

Chemotherapy +

dasatinib, BMT

Chemotherapy +

dasatinib/ imatinib at

relapse

66

4 F/18 B-ALL 110 87/ 92

t(1;9)(q24;q34)

ABL1-rearranged (FISH)

RCSD1-ABL1

NA NA

5 F/15 B-ALL 348 NA/NA 46,XX,t(1;9)(q24;q34)

RCSD1-ABL1

Chemotherapy, BMT

at 4, 35 and 84 months

following relapse.

84 died

6 M/31 B-ALL 146 90/NA

46,XY,t(1;9)(q23;q34),inv(2)(p21q

33)

Developed:

45,XY,t(1;9),inv(2),t(5;16)(q33;q2

4), dic(18;20)(p11;q11) and

46,XY,t(1;9),inv(2),t(5;16),dic(18;2

0),der(19)t(17;19)(q21;p13),+21

RCSD1-ABL1

Chemotherapy,

transient clinical

effects with imatinib,

and dasatinib.

6.5 died

7 M/16 B-ALL 48 NA/ NA RCSD1-ABL1 identified by RNA-

sequence analysis NA NA

8 M/18 B-ALL 470 52/58 46,XY,t(1;9)(q24;q34)

RCSD1-ABL1

No compliance to

therapy 12+

9 M/6 B-ALL 108 NA/ NA

46,XY,t(1;9)(q23;q34)

ABL1-rearranged

RCSD1-ABL1

Chemotherapy +

imatinib, poor response

to chemotherapy

1

10 F/26 B-ALL 26 84/86 46,XX,t(1;9)(q24;q34)

RCSD1-ABL1

Chemotherapy

+dasatinib, BMT,

relapse

Chemotherapy

+ponatinib, BMT

Ponatinib

monotherapy, relapse

25 died

11 F/15 B-ALL 251 45/NA 46,XX,t(1;9)(q24;q34)

IKS deletion

Chemotherapy +

dasatinib BMT 8 died

12 M/15 B-ALL 69 71/95 46,XY,t(1;9)(q31?;q34)

RCSD1-ABL1

Chemotherapy +

imatinib 2 months after

relapse: sustained

clinical remission

163

Abbreviations: WBC., white blood cells; PB., peripheral blood; BM., bone marrow; M., male; F., female; ALL., acute lymphocytic leukemia; * at relapse; BMT., bone marrow transplantation.

1. Gonzales et al., 2004; 2. De Braekeleer et al., 2011; 3. Mustjoki et al., 2009; 4. Zamecnikova et al., 2010; De Braekeleer et al., 2013; 5. De Braekeleer et al., 2011; 6. Inokuchi et al., 2011; 7. Roberts et al., 2012; 8. De Braekeleer et al., 2013; 9. Roberts

et al., 2014; 10. Collette et al.,2015; 11. Kamran et al., 2015; 12. Perwein et al., 2016



Figure 1. Top - courtesy Adriana Zamecnikova and Soad al Bahar: (A) Partial G-banded karyotypes showing the t(1;9)(q24;q34) and fluorescence in situ hybridization with LSI BCR/ABL1 (Vysis/Abott, US) probe showing the split of the ABL1 signal (red). A: Dual-color FISH using RP11-83J21 (labeled in spectrum orange) and RP11-232M22 (labeled in spectrum green) showing two

fusion genes. FISH, fluorescence in situ hybridization. B: Probes. Bottom - courtesy Etienne De Braekeleer and Marc De Braekeleer: R-banded karyotype showing the t(1;9)(q24;q34) translocation. Dual-color FISH using RP11-83J21 (labeled in

spectrum orange). Probes and RP11-232M22 (labeled in spectrum green) showing two fusion genes. FISH, fluorescence in situ hybridization. LSI bcr/abl dual extra-signal (ES) color probe (Abbott, Rungis, France) and BAC Probes. RP11-83J21

(chromosome 9) and RP11-232M22, RP11-928F1, RP11-138P14, RP11-652E14, RP11-64D9 (chromosome 1). All the probes that were used to find the breakpoint on der(1).

RCSD1 (RCSD domain containing 1)

Location

1q24.2

DNA/RNA

Eyers et al. (2005) cloned for the first time the human

RCSD1, which they called CAPZIP. A 416-amino

acid protein was deduced and they calculated a

molecular mass of 44.5 kD. Northern blot analysis

resulted in a major 3.4-kb transcript and a minor 7-

kb transcript that is highly expressed in skeletal

muscle and weakly in cardiac muscle. CAPZIP is

detected in several lymphoid organs, including

spleen, thymus, peripheral blood leukocytes, lymph

node, and bone marrow.

Protein

Eyers et al. (2005) found many properties of rabbit

Capzip. It interacted specifically with the F-actin

capping protein CapZ. This protein was

phosphorylated by : MAPKAPK2 and SAPK3

(MAPK12), on ser108 by SAPK3 and SAPK4

(MAPK13) and on ser68, ser83, and ser216 by JNK1

alpha-1 (MAPK8) in vitro. This team also found that

stress induced by hyperosmotic shock and

anisomycin, a protein synthesis inhibitor, stimulated

the phosphorylation of CAPZIP in human cell lines



and induced the dissociation of CAPZIP from CAPZ

in Jurkat human T cells. This phenomenon may

regulate the ability of CapZ to remodel actin

filament.


Hybrid gene

Description

RCSD1/ABL1. In-frame fusions of first three exons

of RCSD1 to ABL1 exon 4 to 11 and alternatively

spliced RCSD1/ABL1 consisting of the first two

exons of RCSD1 fused to exon 4 of ABL1 lacking

RCSD1 exon 3 (Mustjoki et al., 2009).

Detection

FISH detection.

Fusion protein

Description

The RCSD1/ABL1 fusion gene encode the tyrosine

kinase domain of ABL1. The chimeric protein

contains part of the SH2 domain of ABL1, the SH1

domain (that has tyrosine kinase function), the 3

nuclear localization signal domains, the 3 DNA-

binding regions and the F-actin-binding domain.

Notably, unlike most of the previously described

chimeric genes involving ABL1 that fuse with exon

2 of ABL1 (containing ABL1 exons 2 and 3), the

RCSD1/ABL1 protein contains only a truncated

ABL1 protein starting from the exon 4-encoded

region, therefore retains only a part of the ABL SH2

domain (with tyrosine kinase function), predicting

its association with ALL rather than chronic myeloid

leukemia (Mustjoki et al., 2009; De Braekeleer et al.,

2013; Collette et al., 2015).

Oncogenesis

The RCSD1 gene, which codes a protein kinase

substrate, CapZIP (CapZ-interacting protein), is

found in immune cells, splenocytes and muscle. It is

possible that the interaction between CapZIP and

CapZ affects the cell ability to remodel actin

filament assembly. CapZIP is phosphorylated when

cells are exposed to various cellular stresses, which

activate the kinase cascade. The interaction between

CapZIP and CapZ would be lost when CapZIP is

phosphorylated. So, RCSD1 would be involved in

the remodeling of the actin cytoskeleton, which is an

important step in mitosis. The probable formation of

the ABL1-RCSD1 fusion gene could result in an

alteration of the cellular function by affecting the

cytoskeleton regulation, which could be an

important step in leukemogenesis.

References Collette Y, Prébet T, Goubard A, Adélaïde J, Castellano R,

Carbuccia N, Garnier S, Guille A, Arnoulet C, Charbonier A, Mozziconacci MJ, Birnbaum D, Chaffanet M, Vey N. Drug response profiling can predict response to ponatinib in a patient with t(1;9)(q24;q34)-associated B-cell acute lymphoblastic leukemia. Blood Cancer J. 2015 Mar 13;5:e292

De Braekeleer E, Douet-Guilbert N, Guardiola P, Rowe D, Mustjoki S, Zamecnikova A, Al Bahar S, Jaramillo G, Berthou C, Bown N, Porkka K, Ochoa C, De Braekeleer M. Acute lymphoblastic leukemia associated with RCSD1-ABL1 novel fusion gene has a distinct gene expression profile from BCR-ABL1 fusion. Leukemia. 2013 Jun;27(6):1422-4

Eyers CE, McNeill H, Knebel A, Morrice N, Arthur SJ, Cuenda A, Cohen P. The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ. Biochem J. 2005 Jul 1;389(Pt 1):127-35

González García JR, Bohlander SK, Gutiérrez Angulo M, Esparza Flores MA, Picos Cárdenas VJ, Meza Espinoza JP, Ayala Madrigal Mde L, Rivera H. A t(1;9)(q23.3 approximately q25;q34) affecting the ABL1 gene in a biphenotypic leukemia. Cancer Genet Cytogenet. 2004 Jul 1;152(1):81-3

Inokuchi K, Wakita S, Hirakawa T, Tamai H, Yokose N, Yamaguchi H, Dan K. RCSD1-ABL1-positive B lymphoblastic leukemia is sensitive to dexamethasone and tyrosine kinase inhibitors and rapidly evolves clonally by chromosomal translocations. Int J Hematol. 2011 Sep;94(3):255-260

Kamran S, Raca G, Nazir K. RCSD1-ABL1 Translocation Associated with IKZF1 Gene Deletion in B-Cell Acute Lymphoblastic Leukemia. Case Rep Hematol. 2015;2015:353247

Mustjoki S, Hernesniemi S, Rauhala A, Kähkönen M, Almqvist A, Lundán T, Porkka K. A novel dasatinib-sensitive RCSD1-ABL1 fusion transcript in chemotherapy-refractory adult pre-B lymphoblastic leukemia with t(1;9)(q24;q34). Haematologica. 2009 Oct;94(10):1469-71

Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, McCastlain K, Ding L, Lu C, Song G, Ma J, Becksfort J, Rusch M, Chen SC, Easton J, Cheng J, Boggs K, Santiago-Morales N, Iacobucci I, Fulton RS, Wen J, Valentine M, Cheng C, Paugh SW, Devidas M, Chen IM, Reshmi S, Smith A, Hedlund E, Gupta P, Nagahawatte P, Wu G, Chen X, Yergeau D, Vadodaria B, Mulder H, Winick NJ, Larsen EC, Carroll WL, Heerema NA, Carroll AJ, Grayson G, Tasian SK, Moore AS, Keller F, Frei-Jones M, Whitlock JA, Raetz EA, White DL, Hughes TP, Guidry Auvil JM, Smith MA, Marcucci G, Bloomfield CD, Mrózek K, Kohlschmidt J, Stock W, Kornblau SM, Konopleva M, Paietta E, Pui CH, Jeha S, Relling MV, Evans WE, Gerhard DS, Gastier-Foster JM, Mardis E, Wilson RK, Loh ML, Downing JR, Hunger SP, Willman CL, Zhang J, Mullighan CG. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014 Sep 11;371(11):1005-15

Zámečníkova A. Chromosomal translocation t(1;9)(q24;q34) in acute lymphoblastic leukemia patient involving the ABL1 gene. Leuk Res. 2011 Sep;35(9):e149-50


Zamecnikova A, al Bahar S. t(1;9)(q24;q34) RCSD1/ABL1. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):259-262.





t(3;9)(p13;q34.1) FOXP1/ABL1 Julie Sanford Biggerstaff

Idaho Cytogenetics Diagnostic Laboratory, Boise, ID 83706/ [email protected]


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0309p13q34ID1619.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68265/09-2016-t0309p13q34ID1619.pdf DOI: 10.4267/2042/68265


Abstract

Review on t(3;9)(p13;q34.1) FOXP1/ABL1, with

data on clinics, and the genes involved.

Keywords

chromosome 3; chromosome 9; FOXP1; ABL1; B

Cell Acute Lymphoblastic Leukemia; Follicular

Lymphoma


Disease

Pre-B Cell Acute Lymphoblastic

Leukemia/Lymphoma (ALL) and Follicular

Lymphoma (Ernst et al., 2011; Koduru et al., 1997).

Note

The FOXP1/ABL1 involvement was ascertained

only in the B-ALL case. t(3;9) was found in a sub-

clone and against the background of a complex

karyotype and TP53 gene mutation in the follicular

lymphoma case.


Pre-B cell.

Epidemiology

1 ALL case reported to date: a 16 yo female patient,

and 1 follicular lymphoma case reported to date: a 52

yo male patient.

Cytology

High leukocytosis (>50,000 x 109/L) at diagnosis.

Treatment

For ALL: Standard COALL (German Cooperative

Study Group) protocol for high-risk ALL followed

by Allogeneic BMT; may be sensitive to treatment

with first or 2nd generation tyrosine kinase inhibitors.

Prognosis

Yet unknown; ALL patient was reported in

remission 9 years post diagnosis, but after paternal

origin haplo-identical BMT.

Cytogenetics

Probes

ABL1 should show split signal using the standard

DCDF BCR/ABL1 construct.


FOXP1 (Forkhead box P1)

Location

3p13

Note

Member of forkhead box (FOX) subfamily P;

transcription factor. These proteins play a role in

cell- and tissue-specific gene transcription

regulation.

DNA/RNA

Gene is 176,228 bp with 16 exons; transcribed from

the - strand ; coding region is 171,437 bp with 14

exons.

Protein

At least 12 protein isoforms produced; dimerizes

with FOXP2 and FOXP4 using the leucine-zipper

domain which is required for DNA binding

capability.

Protein locates to the nucleus.

Germinal mutations

t(3;9)(p13;q34.1) FOXP1/ABL1 Sanford Biggerstaff JA


Germline mutations of FOXP1 are associated with

autosomal dominant intellectual disability with

language impairment, with or without autistic

features (MIM phenotype 613670).

ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)

Location

9q34.12

DNA/RNA

Expressed as either 6- or 7-Kb transcript.

Protein

Tyrosine kinase; located in either the nucleus

(shorter transcript) or cytoplasm (longer transcript)

depending on which splice variant is produced

(Chissoe et al., 1995).


Hybrid gene

Note

In the single patient characterized, the in-frame

fusion was confirmed between FOXP1 exon 19

(ENST00000318789) and ABL1 exon 4

(ENST00000318560) (Ernst et al., 2011).

Description

ABL1 exon 4 fused with FOXP1 alternative RNA

isoform (NM_032682).

Detection

RT-PCR

References Chissoe SL, Bodenteich A, Wang YF, Wang YP, Burian D, Clifton SW, Crabtree J, Freeman A, Iyer K, Jian L. Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation. Genomics. 1995 May 1;27(1):67-82

Ernst T, Score J, Deininger M, Hidalgo-Curtis C, Lackie P, Ershler WB, Goldman JM, Cross NC, Grand F. Identification of FOXP1 and SNX2 as novel ABL1 fusion partners in acute lymphoblastic leukaemia. Br J Haematol. 2011 Apr;153(1):43-6

Hamdan FF, Daoud H, Rochefort D, Piton A, Gauthier J, Langlois M, Foomani G, Dobrzeniecka S, Krebs MO, Joober R, Lafrenière RG, Lacaille JC, Mottron L, Drapeau P, Beauchamp MH, Phillips MS, Fombonne E, Rouleau GA, Michaud JL. De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. Am J Hum Genet. 2010 Nov 12;87(5):671-8

Koduru PR, Raju K, Vadmal V, Menezes G, Shah S, Susin M, Kolitz J, Broome JD. Correlation between mutation in P53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin's lymphoma. Blood. 1997 Nov 15;90(10):4078-91


Sanford Biggerstaff JA. t(3;9)(p13;q34.1) FOXP1/ABL1. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):263-264.





t(1;22)(p36;q11) IGL/PRDM16 Jean-Loup Huret

Medical Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021

Poitiers, France. [email protected]





Abstract Review on t(1;22)(p36;q11) IGL/PRDM16

translocations, with data on clinics, and the genes

involved.

Keywords

chromosome 1; chromosome22; t(1;22)(p36;q11);

IGL; PRDM16


Disease

Splenic marginal zone B-cell lymphoma.

Clinics

Only one case to date: a 68-years old male patient,

who died 38 months after diagnosis (Duhoux et al.,

2012).

Cytogenetics


Accompanying abnormalities were: +12, +18 and

t(1;14)(p12;q32).


PRDM16 (PR domain containing 16)

Location

1p36.32

DNA/RNA

11 splice variants

Protein

1276 amino acids and smaller proteins. Contains a

N-term PR domain; 7 Zinc fingers, a proline-rich

domain, and 3 Zinc fingers in the C-term. Binds

DNA. Transcription activator; PRDM16 has an

intrinsic histone methyltransferase activity.

PRDM16 forms a transcriptional complex with

CEBPB. PRDM16 plays a downstream regulatory

role in mediating TGFB signaling (Bjork et al.,

2010). PRDM16 induces brown fat determination

and differentiation. PRDM16 is expressed

selectively in the earliest stem and progenitor

hematopoietic cells, and is required for the

maintenance of the hematopoietic stem cell pool

during development. PRDM16 is also required for

survival, cell-cycle regulation and self-renewal in

neural stem cells (Chuikov et al., 2010; Kajimura et

al., 2010; Aguilo et al., 2011; Chi and Cohen, 2016).

IGL (Immunoglobulin Lambda)

Location

22q11.22


Fusion protein

Oncogenesis

IGL may act as an enhancer of PRDM16.

References Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P,

Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66

t(1;22)(p36;q11) IGL/PRDM16 Huret JL


Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR. Prdm16 is required for normal palatogenesis in mice. Hum Mol Genet. 2010 Mar 1;19(5):774-89

Chi J, Cohen P. The Multifaceted Roles of PRDM16: Adipose Biology and Beyond. Trends Endocrinol Metab. 2016 Jan;27(1):11-23

Chuikov S, Levi BP, Smith ML, Morrison SJ. Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol. 2010 Oct;12(10):999-1006

Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula K, Mozziconacci MJ, Laibe S, Wlodarska I, Michaux L,

Talmant P, Richebourg S, Lippert E, Speleman F, Herens C, Struski S, Raynaud S, Auger N, Nadal N, Rack K,

Mugneret F, Tigaud I, Lafage M, Taviaux S, Roche-Lestienne C, Latinne D, Libouton JM, Demoulin JB, Poirel HA. PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012 Jan;156(1):76-88

Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009 Aug 27;460(7259):1154-8


Huret JL. t(1;22)(p36;q11) IGL/PRDM16. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):265-266.





t(1;3)(p36;q21) RPN1/PRDM16 Jean-Loup Huret







Abstract Review on t(1;3)(p36;q21) translocations, with data


Keywords

chromosome 1; chromosome3; t(1;3)(p36;q21);

RPN1; PRDM16

Identity

A translocation t(1;3)(p36;q21), with the same

breakpoints but involving PSMD2 and PRDM16

probably does not exist: 1- PSMD2 sits in 3q27, while the breakpoint is in

3q21;

2- PSMD2, a protein of the proteasome, is mainly

known in PubMed by its alias: "RPN1", while the

true RPN1, a protein involved in N-glycosylation

and sitting in 3q21, is better known by its full name:

"Ribophorin I".

Hence the confusion, found in a number of papers of

the literature.


Disease

Myelodysplastic syndromes and acute myeloid

leukaemias

Note

A t(1;3)(p36;q21) RPN1/PRDM16 was found in 35

cases (Mochizuki et al., 2000; Shimizu et al., 2000:

Xinh et al., 2003; Duhoux et al., 2012)


There were 19 myeloproliferative/myelodysplastic

syndromes: 1 chronic myeloid leukemia (CML), 3

refractory anaemia with ring sideroblasts (RARS); 6

refractory anemia with excess blasts (RAEB,

RAEB2, RAEB-T), 6 chronic myelomonocytic

leukaemia (CMML) and 3 myelodysplastic

syndrome not otherwise specified (MDS-NOS); and

16, acute myeloid leukaemias; 7 apparently de novo

(AML- M1, M2, M4, M5a, M6 and NOS), and 9

therapy-related or secondary AML.

Clinics

Median age was 66 years (range 29-92). Sex ratio

was 21 male/14 female patients (3/5 male, 2/5

female).

Prognosis

Median survival in 29 patients was 13-15 months;

five patients died within a month after diagnosis,

while 2 patients were long survivors (65 months +

and 80 months+).

Cytogenetics


The t(1;3)(p36;q21) was the sole abnormality in 26

of 35 cases, and accompanied with del(5q) at

diagnosis in 5 cases. In 2 additional cases, the del(5q)

occurred during course of the disease. There was one

del(13q) and one del(20q), markers and a complex

karyotype were found in two cases.

http://documents.irevues.inist.fr/bitstream/DOI%20t0103p36q21ID2048.txt

t(1;3)(p36;q21) RPN1/PRDM16 Huret JL




Location

1p36.32

DNA/RNA

11 splice variants

Protein




DNA.

Transcription activator; PRDM16 has an intrinsic

histone methyltransferase activity.




2010).

PRDM16 induces brown fat determination and

differentiation.

PRDM16 is expressed selectively in the earliest stem

and progenitor hematopoietic cells, and is required

for the maintenance of the hematopoietic stem cell

pool during development. PRDM16 is also required

for survival, cell-cycle regulation and self-renewal in



RPN1 (ribophorin I)

Location

3q21.3

Note

RPN1 (Ribophorin I) (3q21.3, starts at 128338813

and ends at 128369719 bp from pter) must not be

confused with PSMD2 (proteasome 26S subunit,

non-ATPase 2) (3q27.1; starts at 184018369 and

ends at 184026842 bp from pter). PSMD2 aliases

are: RPN1, P97, S2, TRAP2 (see above).

DNA/RNA

8 splice variants

Protein

607 amino acids. RPN1 comprised of a signal

peptide (aa 1-23).RPN1 (Ribophorin I) is an

endoplasmic reticulum transmembrane protein and a

subunit of the oligosaccharyltransferase (OST)

complex. RPN1 regulates the delivery of precursor

proteins to the OST complex by presenting them to

the catalytic core. RPN1 acts as a substrate-specific

facilitator of N-glycosylation It may function as a

chaperone that recognizes misfolded proteins, and

plays a role in protein quality control in association

with MLEC (malectin) (Wilson and High, 2007;

Wilson et al., 2008; Takeda et al., 2014).


Hybrid gene

Description

5' RPN1 translocated to 3' PRDM16. The breakpoint

in PRDM16 is located either in the ?rst intron, or 5'

of exon 1. Transcriptional activation of can occur in

some patients, and fusion transcripts have been

generated in other patients.

t(1;3)(p36;q21) RPN1/PRDM16 Huret JL


Fusion protein

Oncogenesis

The 5' flanking regions of the rat RPN1 gene

containes GC-rich elements and an octamer motif. It

could serve as an enhancer, to activate transcription

of PRDM16 (Mochizuki et al., 2000; Shimizu et al.,

2000). Overexpression of PRDM16 (Duhoux et al.,

2012).

References Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66


Chi J, Cohen P. The Multifaceted Roles of PRDM16: Adipose Biology and Beyond. Trends Endocrinol Metab. 2016 Jan;27(1):11-23


Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula K, Mozziconacci MJ, Laibe S, Wlodarska I, Michaux L, Talmant P, Richebourg S, Lippert E, Speleman F, Herens C, Struski S, Raynaud S, Auger N, Nadal N, Rack K, Mugneret F, Tigaud I, Lafage M, Taviaux S, Roche-Lestienne C, Latinne D, Libouton JM, Demoulin JB, Poirel HA. PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012 Jan;156(1):76-88


Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, Morishita K. A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood. 2000 Nov 1;96(9):3209-14

Shimizu S, Suzukawa K, Kodera T, Nagasawa T, Abe T, Taniwaki M, Yagasaki F, Tanaka H, Fujisawa S, Johansson B, Ahlgren T, Yokota J, Morishita K. Identification of breakpoint cluster regions at 1p36.3 and 3q21 in hematologic malignancies with t(1;3)(p36;q21). Genes Chromosomes Cancer. 2000 Mar;27(3):229-38

Takeda K, Qin SY, Matsumoto N, Yamamoto K. Association of malectin with ribophorin I is crucial for attenuation of misfolded glycoprotein secretion. Biochem Biophys Res Commun. 2014 Nov 21;454(3):436-40

Wilson CM, High S. Ribophorin I acts as a substrate-specific facilitator of N-glycosylation. J Cell Sci. 2007 Feb 15;120(Pt 4):648-57

Wilson CM, Roebuck Q, High S. Ribophorin I regulates substrate delivery to the oligosaccharyltransferase core. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9534-9

Xinh PT, Tri NK, Nagao H, Nakazato H, Taketazu F, Fujisawa S, Yagasaki F, Chen YZ, Hayashi Y, Toyoda A, Hattori M, Sakaki Y, Tokunaga K, Sato Y. Breakpoints at 1p36.3 in three MDS/AML(M4) patients with t(1;3)(p36;q21) occur in the first intron and in the 5' region of MEL1. Genes Chromosomes Cancer. 2003 Mar;36(3):313-6


Huret JL. t(1;3)(p36;q21) RPN1/PRDM16. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):267-269.





t(1;17)(p36;q21) WNT3 or NSF/PRDM16 Jean-Loup Huret







Abstract Review on t(1;17)(p36;q21) translocation, with data


Keywords

chromosome 1; chromosome 17; t(1;17)(p36;q21);

PRDM16; WNT3; NSF


Disease

Acute myeloid leukaemia.

Clinics

Only one case to date, a 5-year-old girl who

presented with acute myeloid leukaemia. She died 6

months after diagnosis (Duhoux et al., 2012).

Cytogenetics


The t(1;17)(p36;q21) was the sole anomaly.

Genes involved and proteins PRDM16, on chromosome 1, was implicated in the

translocation. However, which gene on chromosome

17 is involved in the malignant process is unknown:

two genes are located in the vicinity of the 17q21

breakpoint: WNT3 (44839872 - 44896126 bp from

pter) and NSF (44668035 - 44834828 bp from pter).

WNT3 (17q21.31), 355 amino acids, is one of the 19

known Wnt proteins. They bind a frizzled (Fz)/low

density lipoprotein receptor related protein (LRP)

complex, activating the cytoplasmic protein

dishevelled ( DVL1, DVL2 or DVL3), and the b-

catenin Wnt/beta catenin signaling pathway is

activated (Thorstensen and Lothe, 2003).

NSF (17q21.31), 744 amino acids, is a hexameric

ATPase. NSF catalyzes the fusion of transport

vesicles. Vesicle fusion is driven by specific

associations of complementary SNARE proteins

(soluble NSF attachment protein receptor) residing

on the vesicle (v-SNAREs) and target (t-SNAREs)

membranes. This mechanism involves NSF and its

adaptor protein, NAPA. This rmechanism of vesicle

fusion include endoplasmic reticulum-Golgi

transport, intra-Golgi vesicle fusion, trafficking from

the trans-Golgi network to the plasma membrane,

neuromediator exocytosis, and synaptic vesicle

fusion (Naydenov and Ivanov, 2013).


Location

1p36.32

DNA/RNA

11 splice variants

Protein




DNA. Transcription activator; PRDM16 has an

intrinsic histone methyltransferase activity.




2010). PRDM16 induces brown fat determination

and differentiation. PRDM16 is expressed

selectively in the earliest stem and progenitor

hematopoietic cells, and is required for the

t(1;17)(p36;q21) WNT3 or NSF/PRDM16 Huret JL


maintenance of the hematopoietic stem cell pool

during development. PRDM16 is also required for

survival, cell-cycle regulation and self-renewal in




Fusion protein

Oncogenesis

PRDM16 was not overexpressed (Duhoux et al.,

2012)

References Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66


Chi J, Cohen P. The Multifaceted Roles of PRDM16: Adipose Biology and Beyond. Trends Endocrinol Metab.

2016 Jan;27(1):11-23


Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula K, Mozziconacci MJ, Laibe S, Wlodarska I, Michaux L, Talmant P, Richebourg S, Lippert E, Speleman F, Herens C, Struski S, Raynaud S, Auger N, Nadal N, Rack K, Mugneret F, Tigaud I, Lafage M, Taviaux S, Roche-Lestienne C, Latinne D, Libouton JM, Demoulin JB, Poirel HA. PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012 Jan;156(1):76-88


Naydenov NG ; Ivanov AI.. NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha). Atlas Genet Cytogenet Oncol Haematol. 2014;18(5):301-305.

Thorstensen L; Lothe RA.. The WNT signaling pathway, its role in human solid tumors. Atlas Genet Cytogenet Oncol Haematol. 2003;7(2):144-159.


Huret JL. t(1;17)(p36;q21) WNT3 or NSF/PRDM16. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):270-271.

Cancer Prone Disease Section Review




Fanconi anemia Filippo Rosselli

UMR8200 CNRS, Gustave Roussy Institute, Université Paris-Saclay - Université Paris-Sud;

[email protected]

Published in Atlas Database: April 2016Online updated version : http://AtlasGeneticsOncology.org/Kprones/FAID10001.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68269/04-2016-FAID10001.pdf DOI: 10.4267/2042/68269

This article is an update of : Huret JL. Fanconi anaemia. Atlas Genet Cytogenet Oncol Haematol 2002;6(4) Huret JL. Fanconi anaemia. Atlas Genet Cytogenet Oncol Haematol 1998;2(2)


Abstract Fanconi anemia (FA) is a rare human recessive

syndrome featuring bone marrow failure,

myelodysplasia, and predisposition to cancer as well

as chromosome fragility and hypersensitivity to

DNA interstrands crosslinking agents. FA was

described in 1927 by the Swiss pediatrician

Giuseppe Fanconi, which reported a first family with

three affected sibling presenting developmental

defects and anemia.

FA cells are hypersensitive, at both cellular and

chromosomal levels, to the exposure to DNA

interstrands crosslinking agents, like mitomycin C,

diepoxybutane, cis-platinum or photoactivated

psoralen.

The chromosomal response to DNA interstrands

crosslinks (ICLs)-inducing agents is so typical that

the observation of both the induced frequency of

chromosome aberrations and their type, i.e. tri- and

quadri-radials, is considered the best diagnostic

criteria for FA.

Indeed, looking simply at the clinical hallmarks of

the patients, it is difficult to distinguish FA patients

from several other bone marrow failure syndromes.

Alternatively, since the FA cells need more time to

pass through both G2 and S phases than normal cell,

the analysis by flow cytometry of the over

accumulation of the FA cells in G2 following

exposure to ICL-inducing agents could be a useful

approach for diagnosis.

More recently, molecular and biochemical

approaches looking at gene mutations, proteins

expression and/or post-translational modifications

are used to validate cytogenetics conclusions.

To date 19 different genes (FANC) have been

associated to FA.

The FANC proteins constitute a pathway which

essential function is to deal with replication stress

assuring the transmission of a stable genome from

one cell to the daughters and acting both during

replication, to cope with stalled replication forks, but

also in G2 and M phases, to resolve un-replicated or

not fully replicated regions before telophase.

For review: Duxin and Walter, 2015; Bogliolo and

Surralles, 2015; Walden and Deans, 2014; Soulier

2011; Lobitz and Velleuer, 2006.

Keywords

Fanconi anemia, DNA repair, Replication, Acute

Myeloid Leukemia, Bone Marrow Failure.

Identity Other names

Fanconi pancytopenia

Note

Nineteen genes currently involved (for which bi-

allelic inactivating mutations are retrieved in

affected individual): FANCA, FANCB, FANCC,

BRCA2 (FANCD1), FANCD2, FANCE, FANCF,

FANCG (XRCC9), FANCI, BRIP1

(BACH1/FANCJ) FANCL, FANCM, PALB2

(FANCN), RAD51C (FANCO), SLX4 (FANCP),

ERCC4 (FANCQ/XPF) RAD51 (FANCR), BRCA1

(FANCS), UBE2T (FANCT).


Fanconi anemia Rosselli F.


A: gaps; B: breaks; C: deletion; D: triradials; E: quadriradials; F: complex figures; G: dicentric. Giemsa staining - Jean Loup Huret.

Inheritance

Autosomal recessive and X-linked (for FANCB); the

estimated prevalence is 1 to 5 cases for million

people; with a heterozygous carrier frequency of

around 1/300 people.

Cytogenetics

Inborn conditions

Spontaneous elevated levels of chromatid and

chromosome gaps and breaks, presence of abnormal

figures, in particular triradials and quadriradials. Hypersensitivity to the clastogenic effects of DNA crosslinking agents, like mitomycin C, diepoxybutane or cis-Platin.

Cytogenetics of cancer

Clonal abnormalities were reported in MDS and

AML: in particular: -5/del(5q) and -7/del(7q) .

Other findings slowing of the cell cycle (G2/M transition, with

accumulating of cells in G2)

impaired oxygen metabolism

defective P53 induction


Note

To date 19 complementation groups have been

described (A to T). FANCA represents 60 to 70% of

the patients, FANCC and FANCG (10 to 15% each),

meaning that all the other are extremely rare (less

than 3% each).

In response to DNA damage and together with

several other partners involved in DNA damage

signaling and cell cycle checkpoint activation, the

FANC proteins work long a linear pathway to cope

with the replication stress induced by the presence of

DNA lesions and help in the replication rescue by

homologous recombination based mechanism.

Briefly, FANCA, FANCB, FANCC, FANCE,

FANCF, FANCG and FANCL (with other

companion proteins) assemble on FANCM and meet

UBE2T to monoubiquitinate FANCD2 and FANCI.

Following their monoubiquitination, the

FANCD2/FANCI heterodimer assembles into

subnuclear foci where in a yet undetermined manner

participates to and/or coordinates the elimination of

the lesions and the restart of the stalled replication

fork thanks to the action of the other component of

the FANC pathway, which include structure specific

endonucleases (XPF, SLX4) and homologous

recombination proteins (RAD51, BRCA1, BRCA2,

...)

The pathway, or some of its components, participate

also to transcription regulation, epigentics,

production/response to inflammatory and stress

induced cytokines and interferons.

FANCA (Fanconi anemia, complementation group A)

Location

16q24.3



Note

The gene spans 80kB and contains 43 exons.

FANCA is the most frequently mutated among the

19 known FANC genes: it accounts for more than

60% of the FA patients worldwide.

Alternative splice results in the production of several

transcripts variants encoding different protein

isoforms.

The most representative protein is a polypeptide of

1455-amino acids weighting approximatively 163

kDa.

Present in both cytoplasms and nucleus, the protein

possesses a nuclear localization signal but lacks of

other known regulatory motifs and any biochemical

function was ascribed to it.

FANCA participates to the nuclear FANCcore

complex that hosts the E3 ligase (FANCL) activity

that, in collaboration with the E2 UBE2T,

monoubiquitinates FANCD2 and FANCI in

response to DNA damage. FANCA interacts directly

with FANCG and FAAP20.

Mutations

FANCB (Fanconi anemia complementation group B)

Location

Xp22.2

Note

FANCB is constituted by 10 exons spanning 77kB.

Alternative splicing results in two transcript variants

encoding a same protein of 859-amino acids with a

MW of 98 kDa. Any biochemical function was

reported for the protein.

FANCB aggregates with FANCL and FAAP100 in a

sub-complex that participates to the FANCcore

complex to mediate FANCD2 and FANCI

monoubiquitination in response to DNA damage.

FANCB stabilizes FANCL and needs FANCA to

translocate into thAe nucleus. Mutations in FANCB

are associated to both Fanconi anemia and X linked

VACTERL with hydrocephalus syndromes.

FANCC (Fanconi anaemia complementation group C)

Location

9q22.32

Note

FANCC has been the first FANC gene to be cloned.

It contains 14 exons and codes an ORF of 1677 bp

which translation results in a protein of 558aa,

weighting about 63kDa. The protein, present in both

cytoplasm and nucleus, interacts with FANCE and

FANCF, a subgroup participating to the FANCcore

complex. Any direct biochemical function was

reported for FANCC.

BRCA2 (breast cancer 2, early onset)

Location

13q13.1

Note

The gene contains 27 exons, coding a mRNA which

translation results in a protein of 3418aa, weighting

about 385kDa. The protein is involved in the

homologous recombination process.

FANCD1/BRCA2 contains several repetitions of a

70 aa motif called the BRC motif that mediate



RAD51 interaction. Indeed, FANCD1/BRCA2 is the

cargo that target RAD51 to ssDNA stretches covered

by RPA at DBS. It interacts with several proteins

involved in DNA metabolism, including FANCD2,

FANCN/PALB2, POLH and some components of

the TREX-2 complex. FANCD1/BRCA2 inherited

mutations are associated to the recessive syndrome

Fanconi

anemia while carriers of one inactivated allele are at

risk for breast and ovarian cancer predisposition

following the somatic loss-of-function of the wild-

type allele.

FANCD2 (Fanconi anemia, complementation group D2)

Location

3p25.3

Note

The gene contains 44 exons. FANCD2 encodes a

1,451-amino acid nuclear protein. As several other

FANC proteins, FANCD2 had no known functional

domains. With its major partner, FANCI, FANCD2

is the target of the Ubiquitin-ligase activity of the the

FANCcore complex. In presence of DNA damage or

replication stress, FANCD2 is monoubiquitinated on

K561 and targeted to subnuclear foci where it

colocalize with several DNA repair proteins. It is

phosphorylated by both ATM and ATR. The protein

participate to both replication safeguard and

chromosome fragile sites integrity maintenance.

Interacts directly or indirectly with several proteins,

including, FANCI, FANCE. USP1, MEN1, BRCA1,

BRCA2, phosphorylated FANCG, FAN1 and

DCLRE1B/Apollo.

FANCE (Fanconi anemia, complementation group E)

Location

6p21.31

Note

The gene contains 10 exons. FANCE protein is

constituted by 536 amino-acids weighting

approximatively 59kDa. It contains two Nuclear

Localization Signal (NLS). FANCE forms with

FANCC and FANCF a FANCcore complex sub-

complex. It is required for FANCC nuclear

accumulation and connects the FANCcore complex

to FANCD2 allowing the FANCL/UBE2T-mediated

FANCD2 monoubiquitination. It is phosphorylated

by CHK1 in response to DNA damage. As several

other FANC proteins, FANCE had no known

biochemical functions.

FANCF (Fanconi anemia, complementation group F)

Location

11p14.3

Note

FANCF is an intron-less gene. The protein, long of

374aa, weights 42kDa. FANCF is predominantly

nuclear, where it interacts with FANCE and

FANCC, a subgroup participating to the FANCcore

complex. As a FANCcore complex participant,

FANCF is involved in FANCD2 and FANCI

monoubiquitination. FANCF had no known

biochemical functions.

FANCG (Fanconi anemia, complementation group G)

Location

9p13.3

Note

The gene codes at least two mRNA of 2.2 and 2.5 kb,

which translation results in a major proteins of 622

aa, weighting 68kDa.

It participates to the FANCcore complex and its

phosphorylation on serine 7 is mandatory for its

function inside the complex.

Nevertheless, as for several other FANC proteins

any biochemical function has been attributed to

FANCG. As for the other components of the

FANCcore complex, its presence inside the complex

is mandatory for FANCD2 and FANCI

monoubiquitination and targeting to subnuclear foci.

FANCI (Fanconi anemia complementation group I)

Location

15q26.1

Note

The gene contains 38 exons. The FANCI protein is

long of 1328aa, weights 50kDa and contains 3 NLS.

FANCI is phosphorylated by ATM/ATR and is

monoubiquitinated by the FANCcore complex on

the lys523. It is considered as a functional homolog

of FANCD2. The two proteins forms a heterodimer

that, following their DNA damage- or replication

stress -induced monoubiquitination, relocalizes to

subnuclear foci to optimally restore DNA and rescue

replication in a yet undetermined manner.

BACH1 (BTB domain and CNC homolog 1)

Location

21q21.3

Note

The gene encodes a protein of 1249aa with a

molecular mass de 141kDa. Memeber of the RecQ

DEAH helicase family, FANCJ interact with

BRCA1 participating to the DNA double-strand

breaks repair by homologous recombination.

Germline mutations in FANCJ are associated to

breast and ovarian cancer susceptibility. Biallelic

inheritance results in a Fanconi anemia-like

phenotype.



BRIP1 (BRCA1 interacting protein C-terminal helicase 1)

Location

17q23.2

Note

The gene encodes a protein of 1249aa with a

molecular mass de 141kDa. Member of the RecQ

DEAH helicase family, FANCJ interact with

BRCA1 participating to the DNA double-strand

breaks repair by homologous recombination.

Germline mutations in FANCJ are associated to

breast and ovarian cancer susceptibility. Biallelic

inheritance results in a Fanconi anemia-like

phenotype

FANCL (Fanconi anemia complementation group L)

Location

2p16.1

Note

It codes a proteins of 373 aa, weighting 43 kDa,

containing 3 putative WD40 motifs and a PHD zync

finger motif. The protein could be retrieved in both

cytoplasm and nucleus. FANCL is the catalytic

subunit of the FANCore complex. It has the E3

ubiquitin ligase activity necessary for FANCD2 and

FANCI monoubiquitination. It mediate ubiquitin

release from UBE2T and UBE2W.

FANCM (Fanconi anemia complementation group M)

Location

14q21.2

Note

It code for a protein of 2048aa. Contains an N-

terminal helicase domain ans possess the ability to

translocate on duplex DNA. It belongs to the DEAD

box helicase family. It is hyperphosphorylated by

ATR in response of DNA damage FANCM is

thought be the transporter of the FANCcore complex

along the DNA and, so, it participates de facto to

both FANCD2 and FANCI optimal

monoubiquitination.

PALB2 (partner and localizer of BRCA2)

Location

16p12.2

Note

FANCN contains 13 exons and encodes for a protein

of 1186 aa having a molecular mass of about

130kDa. The protein participates to homologous

recombination in collaboration with its major partner

BRCA2. It interacts also with BRCA1, RAD51,

RAD51C and POLH. Monoallelic PALB2 mutations

confer predisposition to breast and pancreatic

cancers. hereditary bi-allelic mutations in FANCN

result in Fanconi anemia.

RAD51C (RAD51 paralog C)

Location

17q22

Note

Member of the RAD51 gene family, involved in

homologous recombination repair of damaged DNA

and in meiotic recombination. RAD51C encodes a

major 1.3 kB mRNA translated in a protein of 376

aa, weighting approximatively 45kDa. It interact

with several DNA repair proteins, including RAD51

and PALB2.

It participates to several complexes with RAD51B,

RAD51D and XRCC2 or with XRCC3. The

monoallelic inheritance of RAD51C is associated to

breast and ovarian cancers predispostion. The

biallelic, recessive, inheritance of RAD51C

mutations result in a Fanconi anemia-like syndrome.

SLX4 (SLX4 structure-specific endonuclease subunit)

Location

16p13.3

Note

The protein is constituted by 1834 aa which weights

about 200kDa. Component of the SLX1-SLX4

structure-specific endonuclease, it is the docking

platform of a complex assembling two other

structure specific enducleases: XPF-ERCC1 and

MUS81-EME1.

SLX4 is also associated to MSH2/MSH3, the

telomere binding complex TRF2-RAP1 and the

kinase PLK1. FANCP is required DNA repair,

chromosome fragile sites maintenance and for

replication fork failure rescue.

ERCC4 (xeroderma pigmentosum, complementation group F)

Location

16p13.12

Note

The gene contains 11 exons spanning more than 28

kb. The gene encodes 3 mRNA of 2.4, 3.8 and 7 kb,

which translation results in a protein of 905 aa,

having a mass of about 110 kDa. The protein

interacts primarily with with ERCC1 making up the

ERCC1-XPF-5' structure specific endonuclease. The

protein also interacst with FANCP/SLX4. Biallelic

inactivating mutation in this gene have been

associated to Fanconi anemia, xeroderma

pigmentosum, cockayne syndrome and XFE

progeroid syndrome.

RAD51 (RAD51 recombinase)

Location



15q15.1

Note

Belonging to the RAD51 family, this gene is encodes

several transcript variant, the major being a 1.8kb

mRNA which translation results in a protein of

339aa weighting 37kDa which plays a central role in

homologous recobination repair and in meiotic

recombination. It interacts with BRCA1, BRCA2,

RPA, and several other DNA repair proteins. The

only Fanconi anemia patient associated to RAD51

mutation bears a de novo mutation which created a

dominant-negative variant. Mutations in RAD51

have been also associated to breast cancer

suceptibility and to the congenital Mirror

Movements 2 syndrome.

BRCA1 (breast cancer 1, early onset)

Location

17q21.31

UBE2T (ubiquitin conjugating enzyme E2 T)

Location

1q32.1

Note

The gene contains 7 exons. Two transcript variants

encodes different protein isoforms, the major is a

protein of 197 amino acids weighting

approximatively 22kDa. UBE2T is an E2-

conjugating enzyme that collaborates with FANCL,

the E3 ubiquitin ligase hosted by the FANC core

complex, for the monoubiquitination of FANCD2

and FANCI. It interact with FANCL and BRCA1.

References Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A, Trujillo JP, Minguillón J, Ramírez MJ, Pujol R, Casado JA, Baños R, Rio P, Knies K, Zúñiga S, Benítez J, Bueren JA, Jaspers NG, Schärer OD, de Winter JP, Schindler D, Surrallés J. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet. 2013 May 2;92(5):800-6

Bogliolo M, Surrallés J. Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics. Curr Opin Genet Dev. 2015 Aug;33:32-40

Crossan GP, van der Weyden L, Rosado IV, Langevin F, Gaillard PH, McIntyre RE, Gallagher F, Kettunen MI, Lewis DY, Brindle K, Arends MJ, Adams DJ, Patel KJ. Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nat Genet. 2011 Feb;43(2):147-52

Dorsman JC, Levitus M, Rockx D, Rooimans MA, Oostra AB, Haitjema A, Bakker ST, Steltenpool J, Schuler D,

Mohan S, Schindler D, Arwert F, Pals G, Mathew CG, Waisfisz Q, de Winter JP, Joenje H. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol. 2007;29(3):211-8

Duxin JP, Walter JC. What is the DNA repair defect underlying Fanconi anemia? Curr Opin Cell Biol. 2015 Dec;37:49-60

. Positional cloning of the Fanconi anaemia group A gene. Nat Genet. 1996 Nov;14(3):324-8

Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002 Jul 26;297(5581):606-9

Kim Y, Lach FP, Desetty R, Hanenberg H, Auerbach AD, Smogorzewska A. Mutations of the SLX4 gene in Fanconi anemia. Nat Genet. 2011 Feb;43(2):142-6

Lo Ten Foe JR, Rooimans MA, Bosnoyan-Collins L, Alon N, Wijker M, Parker L, Lightfoot J, Carreau M, Callen DF, Savoia A, Cheng NC, van Berkel CG, Strunk MH, Gille JJ, Pals G, Kruyt FA, Pronk JC, Arwert F, Buchwald M, Joenje H.. Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA. Nature genetics. 1996; 14: 320-323

Lobitz S, Velleuer E.. Guido Fanconi (1892-1979): a jack of all trades. Nat Rev Cancer 2006; 6: 893-898. REVIEW

Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, Steltenpool J, Stone S, Dokal I, Mathew CG, Hoatlin M, Joenje H, de Winter JP, Wang W.. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005; 37: 958-963.

Meetei AR, de Winter JP, Medhurst AL, Wallisch M, Waisfisz Q, van de Vrugt HJ, Oostra AB, Yan Z, Ling C, Bishop CE, Hoatlin ME, Joenje H, Wang W.. A novel ubiquitin ligase is deficient in Fanconi anemia. Nat Genet. 2003; 35: 165-170.

Meetei AR1, Levitus M, Xue Y, Medhurst AL, Zwaan M, Ling C, Rooimans MA, Bier P, Hoatlin M, Pals G, de Winter JP, Wang W, Joenje H.. X-linked inheritance of Fanconi anemia complementation group B. Nat Genet. 2004; 36: 1219-12124.

Pinto FO, Leblanc T, Chamousset D, Le Roux G, Brethon B, Cassinat B, Larghero J, de Villartay JP, Stoppa-Lyonnet D, Baruchel A, Socié G, Gluckman E, Soulier J.. Diagnosis of Fanconi anemia in patients with bone marrow failure. Haematologica. 2009; 94: 487-495.

Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, Neveling K, Kelly P, Seal S, Freund M, Wurm M, Batish SD, Lach FP, Yetgin S, Neitzel H, Ariffin H, Tischkowitz M, Mathew CG, Auerbach AD, Rahman N.. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007; 39: 162-164.

Rickman KA, Lach FP, Abhyankar A, et al. Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia. Cell Rep. 2015; 12: 35-41.

Sawyer SL, Tian L, Kähkönen M, Schwartzentruber J, Kircher M; University of Washington Centre for Mendelian Genomics; FORGE Canada Consortium, Majewski J, Dyment DA, Innes AM, Boycott KM, Moreau LA, Moilanen JS, Greenberg RA.. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov. 2015; 5: 135-42.

Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT.. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol. 2007; 14: 564-567. E



Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ.. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007; 129: 289-301.

Soulier J.. Fanconi anemia Hematology Am Soc Hematol Educ Program. 2011;2011:492-7. REVIEW

Stoepker C, Hain K, Schuster B, Hilhorst-Hofstee Y, Rooimans MA, Steltenpool J, Oostra AB, Eirich K, Korthof ET, Nieuwint AW, Jaspers NG, Bettecken T, Joenje H, Schindler D, Rouse J, de Winter JP.. SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat Genet. 2011; 43: 138-141

Strathdee CA, Gavish H, Shannon WR, Buchwald M. Cloning of cDNAs for Fanconi's anaemia by functional complementation. Nature. 1992; 356: 763-767

Timmers C, Taniguchi T, Hejna J, Reifsteck C, Lucas L, Bruun D, Thayer M, Cox B, Olson S, D'Andrea AD, Moses R, Grompe M.. Positional cloning of a novel Fanconi anemia gene, FANCD2. Mol. Cell 2001; 7: 241-248.

Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V, Neveling K, Endt D, Kesterton I, Autore F, Fraternali F, Freund M, Hartmann L, Grimwade D, Roberts RG, Schaal H, Mohammed S, Rahman N, Schindler D, Mathew CG..

Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010; 42: 406-409.

Walden H, Deans AJ. The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder. Annu Rev Biophys. 2014; 43: 257-278. REVIEW

Wang AT, Kim T, Wagner JE, Conti BA, Lach FP, Huang AL, Molina H, Sanborn EM, Zierhut H, Cornes BK, Abhyankar A, Sougnez C, Gabriel SB, Auerbach AD, Kowalczykowski SC, Smogorzewska A.. A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination. Mol Cell. 2015 6; 59: 478-490.

de Winter JP, Rooimans MA, van Der Weel L, van Berkel CG, Alon N, Bosnoyan-Collins L, de Groot J, Zhi Y, Waisfisz Q, Pronk JC, Arwert F, Mathew CG, Scheper RJ, Hoatlin ME, Buchwald M, Joenje H.. The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM. Nat Genet. 2000; 24:15-16.


Rosselli F. Fanconi anemia. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):272-278.




Instructions to Authors

Policies- Instructions to Authors

See http://documents.irevues.inist.fr/bitstream/handle/2042/48486/Instructions-to-authors.pdf

Manuscripts submitted to the Atlas must be submitted solely to the Atlas.

The Atlas publishes "cards", "deep insights", "case reports", and "educational items".

Cards are structured review articles. Detailed instructions for these structured reviews can be found at:

http://AtlasGeneticsOncology.org/Forms/Gene_Form.html for reviews on genes,

http://AtlasGeneticsOncology.org/Forms/Leukaemia_Form.html for reviews on leukaemias,

http://AtlasGeneticsOncology.org/Forms/SolidTumour_Form.html for reviews on solid tumours,

http://AtlasGeneticsOncology.org/Forms/CancerProne_Form.html for reviews on cancer-prone diseases.

According to the length of the paper, cards are divided, into "reviews" (texts exceeding 2000 words), "mini reviews" (between),

and "short communications" (texts below 400 words).

Deep Insights are written as traditional papers, made of paragraphs with headings, at the author's convenience.

Case Reports in haematological malignancies are dedicated to recurrent –but rare- chromosomes abnormalities in

leukaemias/lymphomas; see http://atlasgeneticsoncology.org//BackpageAuthors.html#CASE_REPORTS .

It is mandatory to use the specific "Submissionformfor Case reports":

see http://AtlasGeneticsOncology.org/Reports/Case_Report_Submission.html.

Educational Items must be didactic, give full information and be accompanied with iconography.

Research articlesThe Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.

Authorship All authors should qualify for authorship according to the ICMJE criteria.

Editorial Ethics see http://documents.irevues.inist.fr/bitstream/handle/2042/56068/Policies-editorial-ethics.pdf for: Peer Review Process /

Commissioned papers vs Unsolicited papers /Responsibility for the reviewers / Editorial responsibilities / Conflict of interest-

Competing interests/ Privacy and Confidentiality - Iconography / Protection of Human Subjects and Animals in Research /

Duplicate Publication/ Plagiarism / Retracting a publication

Subscription The Atlas is FREE!

Costs/Page Charge There is NO page charge.

PubMed Central Once the paper online, authors are encouraged to send their manuscript to PubMed Central

http://www.ncbi.nlm.nih.gov/pmc/ with reference to the original paper in the Atlas in

http://documents.irevues.inist.fr/handle/2042/15655

Corporate patronage, sponsorship and advertising

Enquiries should be addressed to [email protected].

Rules, Copyright Notice and Disclaimer

http://documents.irevues.inist.fr/bitstream/handle/2042/48487/Copyright-sponsorship.pdf

Property As "cards" are to evolve with further improvements and updates from various contributors, the property of the cards

belongs to the editor, and modifications will be made without authorization from the previous contributor (who may,

nonetheless, be asked for refereeing); contributors are listed in an edit history manner. Authors keep the rights to use further

the content of their papers published in the Atlas, provided that the source is cited.

Copyright The information in the Atlas of Genetics and Cytogenetics in Oncology and Haematology is issued for general

distribution. All rights are reserved. The information presented is protected under international conventions and under national

laws on copyright and neighbouring rights. Commercial use is totally forbidden. Information extracted from the Atlas may be

reviewed, reproduced or translated for research or private study but not for sale or for use in conjunction with commercial

purposes. Any use of information from the Atlas should be accompanied by an acknowledgment of the Atlas as the source,

citing the uniform resource locator (URL) of the article and/or the article reference, according to the Vancouver convention.

Reference to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, does

not necessarily constitute or imply its endorsement, recommendation, or favouring. The views and opinions of contributors

and authors expressed herein do not necessarily state or reflect those of the Atlas editorial staff or of the web site holder, and

shall not be used for advertising or product endorsement purposes. The Atlas does not make any warranty, express or implied,

including the warranties of merchantability and fitness for a particular purpose, or assumes any legal liability or responsibility

for the accuracy, completeness, or usefulness of any information, and shall not be liable whatsoever for any damages incurred

as a result of its use. In particular, information presented in the Atlas is only for research purpose, and shall not be used for

diagnosis or treatment purposes. No responsibility is assumed for any injury and/or damage to persons or property for any use

or operation of any methods products, instructions or ideas contained in the material herein.

See also "Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical

Publication - Updated October 2004": http://www.icmje.org.

http://AtlasGeneticsOncology.org© ATLAS - ISSN 1768-3262

http://atlasgeneticsoncology.org/Forms/Gene_Form.html

http://atlasgeneticsoncology.org/Forms/Leukemia_Form.html

http://atlasgeneticsoncology.org/Forms/SolidTumor_Form.html

http://atlasgeneticsoncology.org/Forms/CancerProne_Form.html

http://atlasgeneticsoncology.org/BackpageAuthors.html#CASE_REPORTS

http://www.ncbi.nlm.nih.gov/pmc/

http://documents.irevues.inist.fr/handle/2042/15655


http://documents.irevues.inist.fr/bitstream/handle/2042/48487/Copyright-sponsorship.pdf

http://www.icmje.org/

http://www.atlasgeneticsoncology.org/



INIST-CNRS

OPEN ACCESS JOURNAL

vol 21 7 2017documents.irevues.inist.fr/bitstream/handle/2042/68273/vol_21_7_2017.pdf · in...

Documents