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LEUKEMIALEUKEMIAAn An OverviewOverview on on
ComplexComplex DiseaseDiseaseComplexComplex DiseaseDisease
Dr Rosario AngelicaDr Rosario Angelica
LEUKEMIAThe Leukemia is a heterogeneous group ofneoplastic disorders with great variability in clinical course and response to therapy. It isclinical course and response to therapy. It isa fluid cancer that affect hemopoietic stemcells (HSC) in acute leukemia and mature
white blood cells in chronic leukemia.
… LEUKEMIA
The high number of white blood cells is apparent when a blood
sample is viewed under a sample is viewed under a microscope. Frequently, these extra white blood cells are immature or
dysfunctional.
ALL Blood Asportates
Classification
Leukemia is clinically and pathologically subdivided into several large groups. The first division is between myeloid and lymphoblastic Leukemia. In each division it can presented the
acute or chronic forms.acute or chronic forms.In myeloid leukemia it’s involved precursor or
mature of myeloid cellular line, in lymphoid leukemia it’s involved precursor or mature of
lymphoid cellular line in the bone morrow.
Acute leukemiais characterized by the rapid increase of
immature blood cells. This crowding makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute cells. Immediate treatment is required in acute
leukemia due to the rapid progression and accumulation of the malignant cells, which then
spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of
leukemia in children.
…. Acute leukemiaThe involvement of hemopoietic stem cells (HSC) in this disease results in rapid onset and more rapidly fatal without chemioterapic treatments.
Chronic leukemiais distinguished by the excessive build up of relatively mature, but still abnormal, white blood cells. Typically
taking months or years to progress, the cells are produced at a much higher rate than normal cells,
resulting in many abnormal white blood cells in the blood. Whereas acute leukemia must be treated immediately, Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of
therapy. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group.
Four major kinds of leukemia
Types of cellular lines involved:
� Lymphocytic leukemia (or "lymphoblastic")
1. Acute lymphoblastic leukemia (ALL)
2. Chronic lymphoblastic leukemia(CLL)
� Myelogenous leukemia (also "myeloid" or "nonlymphocytic")
1. Acute myelogenous leukemia(AML)
2. Chronic myelogenous leukemia (CML)
Acute lymphoblastic leukemia (ALL)
Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in young children. This disease also affects adults, especially those age 65
and older. Standard treatments involve chemotherapy and radiation. The survival rates chemotherapy and radiation. The survival rates vary by age: 85% in children and 50% in adults.
Subtypes include precursor B acute lymphoblasticleukemia, precursor T acute lymphoblasticleukemia and acute biphenotypic leukemia
Chronic lymphoblastic leukemia(CLL)
Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It
sometimes occurs in younger adults, but it almost never affects children. Two-thirds of almost never affects children. Two-thirds of
affected people are men. The five-year survival rate is 75%. It is incurable, but
there are many effective treatments. One subtype is B-cell prolymphocytic leukemia.
Acute myelogenous leukemia(AML)
Acute myelogenous leukemia (AML) occurs more commonly in adults than in children, and more commonly in men than women. AML is treated with chemotherapy. The AML is treated with chemotherapy. The
five-year survival rate is 40%. Subtypes of AML include acute promyelocytic leukemia,
acute myeloblastic leukemia, and acute megakaryoblastic leukemia
Chronic myelogenous leukemia
Chronic myelogenous (or myeloid) leukemia(CML), also known as chronic granulocytic
leukemia (CGL), is a form of leukemia characterized by the increased and unregulated growth of by the increased and unregulated growth of
predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is
a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes (neutrophils,
eosinophils, and basophils) and their precursors is the main finding
Four General Type of Leukemia
(ALL)
Acute Lymphoblastic
Leukemia (CLL)
Chronic Lymphoblastic
Leukemia
(AML)
Acute Myeloid
Leukemia(CML)
Chronic Myeloid
Leukemia
M6 M7
M4L3
M3
M0
M5
M2
M1L2L1
CML & Myeloma CLL & Lymphoma
Causes and risk factors
There is no single known cause for all of the different types of leukemia. The different leukemias likely have different
causes. Known causes include natural and artificial ionizing radiation, viruses such as Human T-lymphotropicvirus, and some chemicals, notably benzene and alkylatingchemotherapy agents for previous malignancies. Leukemia, chemotherapy agents for previous malignancies. Leukemia,
like other cancers, results from somatic mutations in the DNA which up-regulate oncogenes or down-regulate tumor suppressor genes, and disrupt the regulation of cell death,
differentiation or division.
… Symptoms� Generalised weakness and fatique� Anemia� Frequent or unexplained fever and infections� Weight loss and/or loss of appetite� Excessive and unexplained bruising� Bone pain, joint pains (caused by the spread of "blast" cells to the surface of
the bone or into the joint from the marrow cavity)the bone or into the joint from the marrow cavity)� Breathlessness� Enlarged lymphonodes, liver and/or spleen� Pitting edema (swelling) in the lower limbs and/or abdomen� Petechiae, which are tiny red spots or lines in the skin due to low platelet
levels� the normal bone marrow cells with higher numbers of immature white blood
cells, results in a lack of blood platelets, which are important in the blood clotting process.
The close association of specific chromosome rearrangements and point mutations in all subtypes of human leukemia, lymphoma and
myeloma has been established by a myeloma has been established by a number of investigators during the
past decade.
These differences may reflect differences in the mechanisms involved in the formation of the
translocations. Specific chromatin structural elements, such as in vivo topoisomerase II (topo II) cleavage sites,
DNase I hypersensitive sites and scaffold attachment regions (SARs) have been mapped in the breakpoint regions of the relevant genes. Strong in vivo topo II
cleavage sites and DNase I hypersensitive sites often co-cleavage sites and DNase I hypersensitive sites often co-localize with each other and also with many of the BCRsin most of these genes, whereas SARs are associated with BCRs in MLL, AF4, AF9, AML1, ETO and ABL, but
not in the BCR gene.
A few of the genes involved in these rearrangements and mutations
have already been identified. The identity of all genes affected by
these mutations contribute to shiftthese mutations contribute to shiftthe normal balance to neoplastic
phenotype.
This gene mutations can be clustered in treegroups:
�Mutations affecting genes that contribute to cell proliferation in signal trasductionpathways(FLT3, c-KIT, RAS, Tyrosine-kinase, Ser/Thr kinase);kinase, Ser/Thr kinase);
�Mutations affecting genes involved in hematopoietic differentiation (AML1/ETO);
�mutations affecting genes implicated in cell cycle regulation and/or apoptosis (P53, BCL, HDAC1 and MLL).
c-myc is translocated to the IgG locus,which results in its activated expression
c-myc IgGIgG enhancerc-myc is activated bythe IgG enhancer in
lymphocytes
bcr-abl fusion protein is produced,which results in a constitutively active abl kinase
bcr-abl
bcr
abl
lymphocytes
Correlation between genotype e prognosis
� Pathologically-Complex Cariotypewith autosomal trisomies and/or monosomies
� Translocations and/or Point Mutations in genes as FLT3, NMP
Unfavorable Prognosis
Intermidiate PrognosisMutations in genes as FLT3, NMP
and c-KIT
� Translocations as t(8;21), t(15;17) e inv(16)
Prognosis
Favorable Prognosis
In addition, the resistance profile of patients in CR are divided into three groups based on other different trends. The parameters considered for the division are:
• Cytogenetic Variation pre-chemotherapy in leukemic cells;
• Amount harvest of HSC during mobilization of • Amount harvest of HSC during mobilization of peripheral blood in chemotherapy;
• Minimal Residual Disease (MRD) found in bone marrow biopsies in CR;
• Survival mean in CR.• Relapse Rate CIR
During chemotherapy, treatment for HSCmobilization of Hematopoietic line is
performed. From cell-mobilized harvest it observed that patients mobilize in different
amount, showing correlation between prognosis and peak-harvest height. Patients prognosis and peak-harvest height. Patients with poor prognosis showed a highest peak of HSC mobilized than the other two. Those with a favorable prognosis had a peak lower
than the other two groups.
Nei pazienti con AML la mobilizzazione di un alto numero di CD34+ è
stato inoltre associata con la persistenza di un’elevata quantità di
MRD. La presenza di quest’ultima è attribuibile anche alla presenza
dello stroma che protegge queste cellule dalla chemioterapia. dello stroma che protegge queste cellule dalla chemioterapia.
In letteratura abbiamo riscontrato che in pazienti con una prognosi
favorevole la quantità di MRD si attestava intorno allo 0,1% che è di
molto inferiore ai livelli riscontrati in pazienti con prognosi
sfavorevole.
SUMMARYSUMMARYFeatures Good Risk Intermediate Poor Risk
MRD Low Intermediate High
harvested HSC peak
Low intermediate High
CIR Low Intermediate High
DFS High Intermediate Low DFS
High
Intermediate
Low
Response to drugs Post-Chemotherapy
High Responive Normal Responsive Low Responsive
Molecular FeaturesMolecular FeaturesMolecular FeaturesMolecular Features
A chromosome translocation that forms Bcr-Abl
in a hematopoietic stem cell forms the diagnostic
“Philadelphia” chromosome and results in the
initial chronic phase of human chronic
myelogenous leukemia (CML), characterized by
an expansion in the number of well-
differentiated granulocytes, a type of white blood
cell. cell.
A second mutation in one such cell (e.g., in p53)
leads to acute leukemia.
The chromosomal translocation results in fusion of a portion of the bcr gene (whose function is unknown but whose N-terminal segment forms a coiled-coil domain that links several bcr polypeptides together) with part of the c-abl gene,
which encodes a protein-tyrosine kinase whose normal substrates are not known.
The chimeric polypeptides expressed from the resulting Bcr-Abl oncogene form a tetramer that exhibits constitutive Abl kinase activity.
Although Abl is normally localized to the nucleus, addition of the Bcr segment causes the Bcr-Abl oncoprotein to be localized to the cytosol. causes the Bcr-Abl oncoprotein to be localized to the cytosol.
Bcr-Abl binds to many intracellular signal-transduction proteins and then phosporylates them, proteins that Abl would not normally activate.
As a consequence, these signaling proteins become activated in the absence of growth factors.
Proliferation
ProliferationProliferation
Diffuse large B cell lymphoma (non-Hodgkin's lymphoma)
It consists of heterogeneous group of B cell lymphomas which is not characterized by the presence of a single
translocation but has a variety of chromosomal abnormalities. The most common translocations
occurring in DLBL involve the BCL6 gene (TF) and theoccurring in DLBL involve the BCL6 gene (TF) and theBCL2 gene. Other chromosomal translocations include the
t(14;15)(q32;q11–13), t(1;22)(q22;q11), t(1;14)(q21;q32), and t(10;14)(q24;q32) and involve the genes BCL8,
FCGRIIb, MUC1 and NfκB2, respectively. These translocations do not result in fusion proteins but rather
result in the juxtaposition of oncogenes with the immunoglobulin gene (Ig) loci.
Chromosomal rearrangements or translocations
Neoplasm Translocation Proto-oncogene
Burkitt lymphoma t(8;14) 80% of cases c-myc1
t(8;22) 15% of casest(2;8) 5% of cases
Chronic myelogenous t(9;22) 90-95% of cases bcr-abl2
leukemialeukemia
Acute lymphocytic t(9;22) 10-15% of cases bcr-abl2
leukemia
1c-myc is translocated to the IgG locus, which results in its activated expression2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase
Acute Lymphoblastic LeukemiaALL is characterized by the presence of various
chromosomal translocations that lead to the altered expression patterns of the HOX family
genes, which code for transcription factors regulating genes involved in haematopoieticregulating genes involved in haematopoietic
stem cell differentiation.
…Acute Lymphoblastic Leukemia
Mixed lineage leukemia (MLL) protein is another member of the HOX regulatory pathway. It is a nuclear
protein that regulates the expression of various members of the HOX family. Translocations involving MLL lead to the formation of chimeric proteins whichMLL lead to the formation of chimeric proteins which
consist of the N-terminal portion of MLL fused to the C-terminal portion of more than 40 partners. This
genetic alteration results in increased transcriptional activity, which disrupts the normal pattern of HOX
gene expression and further affects the haematopoieticstem cell growth pattern.
MLL
4q35.1 SORBS2
AFX1
4q35.1 SORBS2
CREBBP
MLLT6RARa
EP300
c-myc is translocated to the IgG locus,which results in its activated expression
c-myc IgGIgG enhancer
c-myc is activated bythe IgG enhancer in
lymphocytes
The ALL traslocations (8;14)(q24;q32), t(8;22)(q24;q11) and t(2;8)(p12;q32) are all traslocations that come at the fusion gene between c-myc and Ig (respectivelyIgH, IgL and IgK).
This fusion genes are regulated from Ig promoter, whichin the B- & T-cells is many expressed, leading, likein the B- & T-cells is many expressed, leading, likethat, at overexpression of transcription factor c-myc.
Therefore, the limphocites are continually in proliferation, leading at Burkitt’s lymphoma.
Conversion of the c-myc proto-oncogene into an oncogene can occur by several different mechanisms.
…Acute Lymphoblastic Leukemia
The t(12;21)(p12–13;q22) translocation creates a fused gene that includes the 5′ portion of TEL and almost the entire coding region of another
transcription factor gene, AML1. The fusion protein transcription factor gene, AML1. The fusion protein recruits histone deacetylases, which results in
transcriptional repression of many of its target genes. This could lead to alterations in the self-renewal and differentiation abilities of haematopoietic stem cells.
Acute Myeloid leukemiaIn the t(8;21), AML1 is fused to the ETO (MTG8) gene resulting in a
hybrid AML1/ETO mRNA which in turn is translated into achimeric protein.
AML1 encodes the a subunit of the human core binding actor(CBF), a heterodimeric TF complex formed by two unrelatedpolypeptides.
The CBF binds the promoter/enhancer regions of T cell receptorThe CBF binds the promoter/enhancer regions of T cell receptorgenes, G-CSF,GM-CSF, myeloperoxidase, IL5 and IL3.
AML1-ETO transactivates the human c-jun promoter through theproximal activator protein (AP-1)sit e by activating the JNKpathway.
The AML1/ETO fusion gene retains the ability to dimerize with theCBFb subunit and to interact with the enhancer core DNAsequence, blocking the expression of target genes, but not theproliferation.
AML1/ETO
Proliferation
IDTTKD
FLT3
TKD
JMD C-KIT
Block ofapoptosis
Mutationsin codons12 -13-61
K-RASN-RASH-RAS
Block ofdifferentiation
Proliferation
PML-RARA
AML1-ETO
12 -13-61
The inv(16)(p13q22) or t(16;16)(p13;q22), one of the most frequent chromosome abnormalities in AML and specifically associated with AML-M4with abnormal eosiophils [40], results in the fusion of the
CBFB gene at 16q22 and the MYH11 gene at 16q13. Mouse model studies also showed that the CBFB/MYH11 results in a block of
definitive hematopoieisis during embryogenesis and embryonic lethal hemorrhage, similar to the phenotype observed in the AML1-ETO
knock-in mice.These studies showed that CBF has a critical regulatory role in normal These studies showed that CBF has a critical regulatory role in normal
hematopoiesis. Both the t(8;21) and inv(16) result in the abnormal repression of the CBF target genes, although the leukemia cells with
each translocation have distinctive different morphologies
Inappropriate expression of nuclear transcription factors can induce transformation.
49
c-Myc
The CEBPA gene encodes a transcription factor playing a crucial role during differentiation of various cell types including hematopoietic cells. In hematopoiesis, CEBPA plays a pivotal role in early stages of myeloid differentiation and is particularly expressed in myelomonocytic cells. CEBPA acts in multiple ways: by down regulation of c-MYC expression allowing differentiation, by upregulation of the expression allowing differentiation, by upregulation of the expression of granulocytic lineage-specific genes, and by synergistic action with other key genes involved in myeloid development, including CBF complex genes.
The CEBPA interactions are p21, CDK2, CDK4 and E2F; this protein inhibits
cell proliferation by activating transcription of p21/waf1, by
stabilizating p21, by inhibiting CDK2 stabilizating p21, by inhibiting CDK2 and CDK4. The loss of CEBPA function facilitate leukemogenesis by blocking granulocytic differentiation in AML.
CEBPACell
Proliferation
The TP53 gene is a tumor suppressor gene located in 17p13that acts as the ‘guardian of the genome’. Many diversecellular events, including DNA damage and hypoxia,activate the TP53 gene. The P53 protein functions as atranscription factor, regulating downstream genes involvedin cell cycle arrest, DNA repair and programmed cell death.Loss of P53 function confers genomic instability, impairedapoptosis and diminished cell cycle restraint. In AML, P53apoptosis and diminished cell cycle restraint. In AML, P53can be inactivated by deletion or point mutations, whichare generally missense mutations, involving almostexclusively exons 4–8 of the gene. In de novo AML, single-base substitutions at G-C pairs represent the most frequentmutations, but, compared with t-AML and otherhematological malignancies or solid tumors, themutational spectrum does not show a unique pattern.
Arrest cell-cycle
APOPTOSIS
G1-Arrest
G2-Arrest
APOPTOSIS
CancerCancer TreatmentsTreatments::
•• ANTICANCER DRUGS;ANTICANCER DRUGS;
•• SmallSmall MoleculeMolecule InhibitorsInhibitors;;•• SmallSmall MoleculeMolecule InhibitorsInhibitors;;
•• MonoclonalMonoclonal AntibodiesAntibodies
((MAbsMAbs).).
ApprovedApproved byby U.S. U.S. FoodFood and and DrugDrug AdministrationAdministration (FDA).(FDA).
For decades, the hallmark of medical treatment for cancer has been intravenous
cytotoxic chemotherapy. These drugs target rapidly dividing cells, including
cancer cells and certain normal tissues. As cancer cells and certain normal tissues. As a result, many patients experience the
classic toxicities of alopecia, gastrointestinal symptoms, and
myelosuppression.
EFFECTs OF THE MAFOSFAMIDE
59
Ser 20Ser 15
Ser 27
60
The t(15;17) results in a fusion between PML at 15q22 and RARA at 17q21 .
PML is phosphoprotein localizes to nuclearbodies where it functions as a transcriptionfactor and tumor suppressor. Its expression iscell-cycle related and it regulates the p53cell-cycle related and it regulates the p53response to oncogenic signals. The gene isoften involved in the translocation with theretinoic acid receptor alpha gene associatedwith acute promyelocytic leukemia (APL).
RARA is a member of the steroid hormone receptor superfamily and
mediates the
effect of retinoic acid at specific response elements. APL is response elements. APL is characterized by unusual
sensitivity to differentiation by retinoids, such as ATRA.
PML
PMLArsenic Trioxide
BCL-2 ANTISENSE OLIGONUCLEOTIDES
Antisense oligonucleotides (G3139) directed against Bcl-2 promote the degradation of
endogenous Bcl-2 mRNA and thereby decrease intracellular levels of this protein. Preclinical studies have demonstrated that Preclinical studies have demonstrated that Bcl-2 antisense oligonucleotides decrease
the BCL-2 protein livels inducing apoptosis and sensitize AML cell lines and primary
patient samples to chemotherapy.
In contrast, targeted therapy blocks the proliferation of cancer cells by interfering with specific molecules required for tumor development and growth. Some of these molecules may be present in normal tissues, but they are often mutated or overexpressed in
Monoclonal Antibodies as Targeted Therapy
but they are often mutated or overexpressed in tumors.
Among the earliest targeted therapies were antibodies directed against the cell surface markers cluster of differentiation 20 (CD20), CD33, and CD52, which are present on lymphoma and leukemia cells.
The molecular pathways most often targeted in the treatment of solid tumors (e.g., breast, lung, and colorectal cancers) are those of the epidermal growth factor receptor (EGFR, also known as
HER1), vascular endothelial growth factor (VEGF), and HER2/neu.(VEGF), and HER2/neu.
Such pathways can be inhibited at multiple levels: by binding and neutralizing ligands, by occupying
receptor-binding sites, by blocking receptor signaling within the cancer cell; or by interfering
with downstream intracellular molecules.
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Features, Treatment, and Prognosis of Specific Lymphoid Malignancies.
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