Cancer Genetics and Cytogenetics 145 (2003) 82–85

Short communication

Constitutional pericentric inversion of chromosome 9and acute leukemia

Yi-Kong Keunga,*, Mary Ann Knovicha, Bayard L. Powella, David H. Bussb,Mark Pettenatic

aDepartment of Internal Medicine, Comprehensive Cancer Center of Wake Forest University Medical Center, Winston-Salem, NCbDepartment of Pathology, Wake Forest University, School of Medicine, Winston-Salem, NCcDepartment of Pediatrics, Wake Forest University, School of Medicine, Winston-Salem, NC

Received 12 December 2002; received in revised form 15 January 2003; accepted 22 January 2003

Abstract In view of the recent reports demonstrating delayed engraftment after autologous and allogeneictransplantation from donors with constitutional pericentric inversion of chromosome 9, [inv(9)], weconducted a retrospective study on six patients with acute leukemia and inv(9) to investigate ifthere is an impaired engraftment potential of the inv(9) hematopoietic stem cells. All but one of ourpatients had poor outcome. The hematopoietic recovery after induction chemotherapy was notprolonged. It is possible that the hematopoietic defects of inv(9) become more apparent after repeatedcourses of chemotherapy. Alternatively, the number of patients in our series may have been toosmall to detect a partial hematopoietic defect in patients with constitutional inv(9). Larger studiesare required to confirm our findings. � 2003 Elsevier Inc. All rights reserved.

1. Introduction

The incidence of constitutional chromosomal abnormalit-ies in apparently normal individuals has shown an increasein recent years probably because of improved banding tech-niques [1,2]. Constitutional pericentric inversion of chromo-some 9 [inv(9)] involving the secondary constriction regionoccurs in approximately 0.8%–2% of the normal popula-tion and has long been considered a normal variant [1,3,4].However, recent reports have demonstrated delayed en-graftment after autologous and allogeneic transplantationfrom donors with inv(9) suggesting an impaired engraftmentpotential of the inv(9) hematopoietic stem cells [15,16]. Inaddition, we also encountered a patient with acute myelo-cytic leukemia (AML) and constitutional inv(9) who devel-oped prolonged transfusion-dependent pancytopenia for ninemonths after consolidation chemotherapy. The pancytopeniaonly resolved after allogeneic bone marrow transplantation

* Corresponding author. Section on Hematology and Oncology,Department of Internal Medicine, Comprehensive Cancer Center of WakeForest University, Medical Center Boulevard, Winston-Salem, NC 27157.Tel.: (336) 716-7972; fax: (336) 716-5687.

E-mail address: ykeung@wfubmc.edu (Y.-K. Keung).

0165-4608/03/$ – see front matter � 2003 Elsevier Inc. All rights reserved.doi: 10.1016/S0165-4608(03)00055-4

from an HLA-matched unrelated healthy donor [5]. In orderto study the hypothesis of inv(9) individuals possibly havinga latent impaired hematopoiesis, we conduct a retrospectivestudy of the outcome of patients with acute leukemia andinv(9) at our institution.

2. Patients and methods

Approval from the Institutional Review Board to conductthis retrospective study and chart review was obtained. Con-secutive cases of acute leukemia with constitutional inv(9)were identified from the databases of Hematopathology andCytogenetic laboratories. Clinical data, such as demographicinformation, chemotherapy, remission status, hematopoi-etic recovery after induction chemotherapy, and clinical out-come were then extracted from the inpatient andoutpatient records.

3. Results

From January 1988 to December 1998, a total of 799 adultcases of acute leukemia were diagnosed at our institution. Ofthese, six cases (0.8%) were identified to have constitutional

Y.-K. Keung et al. / Cancer Genetics and Cytogenetics 145 (2003) 82–85 83

inv(9), consisting of four females and two males; five caseswere AML and one case was acute biphenotypic leukemia.

3.1. Case 1

A 41-year-old African-American male presented in Janu-ary 1992 with flu-like symptoms and high fever. His whiteblood cell (WBC) count was 3600/µL, hemoglobin was 8.0g/dL, and platelet count was 137,000/µL, and no circulatingblasts. Bone marrow examination revealed 100% cellularitywith over 25% myeloperoxidase-positive blasts weakly posi-tive for myeloperoxidase and Sudan black, and positive forboth L26 (CD20) and MB2 (B-cell marker) immunostaining,confirming the diagnosis of acute biphenotypic leukemia.

Cytogenetic study of the bone marrow revealed the karyo-type 47,XY,�1,�2,�15,�19,�19,del(3)(q22q25),del(7)(p11p22),del(8)(p21p23),(p11q13)c,del(9)(q13q22),�add(2)(q33),�der(19)t(1;19)(q23;p13),�add(19)(q13),�r[2]/46,XY,inv(9)(p11q13)c[18].

He received ara-C, daunorubicin, vincristine, and predni-sone for induction, and complete remission was achievedon day 30. Repeated bone marrow cytogenetic study threemonths later showed the karyotype 46,XY,inv(9)(p11q13)c.He completed consolidation chemotherapy and remainedwell 5 years after initiation of therapy.

3.2. Case 2

A 56-year-old Caucasian female presented in December1994 with acute febrile illness fever, generalized arthralgia,and rapidly enlarging lymphadenopathy. Her WBC was68,500/µL, hemoglobin was 10.4 g/dL, platelet count was37,000/µL, and 56% circulating blasts. Bone marrow exami-nation revealed 80%–100% cellularity with 91% blasts. Themarrow was negative for myeloperoxidase and PAS stainingand positive for butyrate esterase stain. Flow cytometry ofthe bone marrow revealed blasts positive for CD7, CD34,CD38, and HLA-DR, but negative for CD5, CD10, CD19,CD20, CD13, CD15, and CD33. The patient was diagnosedby with AML M0 with aberrant lymphoid marker CD7.

Cytogenetic study of the bone marrow showed47,XX,inv(9)(p11q13)c,�13[8]/46,XX,inv(9)(p11q13)c[12].

She developed left parotid abscess caused by Staphylo-coccus aureus, which was drained. Subsequently she re-ceived ara-C, daunorubicin, vincristine and prednisone forinduction. She succumbed to uncontrolled sepsis by day 21.

3.3. Case 3

A 62-years old African-American female presented inJune 1996 with multiple skin bruises and gross hematuria.Her WBC was 73,700/µL, Hgb was 9.1 g/dL, platelet countwas 25,000/µL, and 56% circulating promyelocytes andblasts. Prothrombin time was 15.6 seconds, activated partialthromboplastin time 23 seconds, fibrinogen 199 mg/dL, andd-dimer was markedly elevated to 32,000-64,000 ng/mL.Bone marrow examination revealed over 95% cellularity

with 91% promyelocytes and blasts consistent with acute pro-myelocytic leukemia (APL) was confirmed by cytogeneticresults: 46,XX,inv(9)(p11q13)c,t(15;17)(q22;q11~q21) [20].

The patient received oral all-trans-retinoic acid (ATRA),daunorubicin, and ara-C, as well as low dose heparin. Shedeveloped ATRA syndrome with respiratory failure requir-ing intubation. Her hospital course was complicated bystaphylococcus septicemia and fungemia caused by toru-lopsis glabrata. She died four weeks after admission.

3.4. Case 4

A 67-year-old Caucasian female presented in January1997 with progressive anasarca and pancytopenia. Her WBCwas 1600/µL, Hgb was 9.5 g/dL, platelets count was 14,000/µL, and no circulating blasts. Prothrombin time was 14.8seconds, activated partial thromboplastin time was 32 sec-onds, fibrinogen 165 mg/dL, and d-dimer was elevated to8000–16,000 ng/mL. Bone marrow examination revealedover 95% cellularity with 93% promyelocytes and blastsconsistent with APL was confirmed by cytogenetic results:46,XX,inv(9)(p11q13)c,t(15;17)(q22;q21)[12]/46,XX,inv(9)(p11q13)c[8].

Peritoneal fluid was transudative with normal cytology.The patient received oral ATRA, daunorubicin, and ara-C.Five weeks later repeat bone marrow examination showedhypocellular marrow without significant blasts or promyelo-cytes. Unfortunately she died of progressive hepatic failureand renal failure secondary to cryptogenic micronodularliver cirrhosis and acute tubular necrosis, which was con-firmed by autopsy 7 weeks after diagnosis.

3.5. Case 5

A 69-years old Caucasian male presented in June 1997with progressive dyspnea. His WBC was 18,900/µL, Hgb was8.9 g/dL, platelet count was 36,000/µL, and 94% circulatingblasts. Bone marrow examination revealed 90%–100% cel-lularity with 99% butyrate esterase-positive blasts consistentwith AML M5.

Cytogenetic study of the bone marrow showed 47,XY,�8,inv(9)(p11q13)c,t(9;11)(p21;q23)[20].

He received ara-C and mitoxantrone for induction andachieved a complete remission. Repeat bone marrow cytoge-netic study showed 46,XY,inv(9)(p11q13)c. He receivedconsolidation chemotherapy with two cycles of intermediatedose ara-C. Unfortunately, his leukemia recurred with CNSinvolvement 3 months after remission, and he died 7 monthsafter diagnosis.

3.6. Case 6

A 78-year-old Caucasian male presented in October 1997with bilateral pneumonia 4 months after diagnosis of refrac-tory anemia with excess of blasts. His WBC was 34,200/µL,Hgb was 9.3 g/dL, and platelet count was 15,000/µL with 47%blasts. Bone marrow examination revealed 80%–100%

Y.-K. Keung et al. / Cancer Genetics and Cytogenetics 145 (2003) 82–8584

Table 1Summary of clinical outcome of acute leukemia associated with constitutional inv(9)

Days toDays to plate-

Case no. Sex/age Diagnosis ANC � 500a let � 20a Treatment outcome

1 F/41 Acute biphenotypic leukemia 28 11 Disease-free at 5 years2 F/56 AML-M0 — — Died of sepsis in 3 weeks3 F/62 AML-M3 — — Died of ATRA syndrome and sepsis

at 4 weeks4 F/67 AML-M3 21 22 Died of hepatic failure at 7 weeks5 M/69 AML-M5 39 37 Died of leukemia at 7 months6 M/78 AML-M2 — — Died of pneumonia in 3 weeks

a Number of days after induction chemotherapy to recover ANC � 500/µL and platelet � 20,000/µL without transfusion.

cellularity with 64% myeloperoxidase-positive blasts con-sistent with AML M2. Flow cytometry of the bone marrowrevealed blasts positive for CD13, CD33, and CD34, andnegative for lymphoid markers.

Cytogenetic study of the bone marrow revealed 47~49,XY,�3,�5,�8,�8,inv(9)(p11q13)c,add(13)(p11.2),�15,�19,�r,�mar1,�mar2,�mar3,�mar4[cp20].

He received ara-C and daunorubicin as induction chemo-therapy. His condition deteriorated and he succumbed 3weeks after diagnosis of AML.

The hematopoietic recovery after induction chemother-apy, the number of days to absolute neutrophil count(ANC) � 500/µL, and the platelet count � 20,000/µL with-out transfusion, were also recorded.

Cases 2, 3, and 6 could not be evaluated because of earlymortality. The mean days to ANC recovery was 29 (range21–39) days, and platelet recovery was 23 (range 11–37)days. All but one of our patients had unfavorable outcome.The clinical outcome is summarized in Table 1.

4. Discussion

Although it is generally regarded as a “normal” variant,inv(9) has been implicated with infertility, recurrent abortion[6–8], and more recently with schizophrenia [9,10], bipolardisorder [11], and myotonic dystrophy [12]. A case ofchronic myelomonocytic leukemia with 46,X,�Y,t(1;9)(q12;q13),�der(9)t(1;9)(q12;q13) has been described in apatient with an inv(9) constitutional karyotype [13]. In-creased heterochromatin polymorphism involving chromo-some 9 has been associated with AML [14] and acutelymphoblastic leukemia (ALL) [15]. Despite the prevalentoccurrence of inv(9), there are very few reports of acuteleukemia in these individuals.

Since cytogenetic studies of the bone marrow are rou-tinely performed in patients with acute leukemia, the preva-lence of inv(9) can be accurately estimated in this group ofpatients. Despite the speculation of previous studies [14,15],our study did not show any increased tendency of individu-als with inv(9) to develop acute leukemia since the preva-lence of constitutional inv(9) among acute leukemia patientsis similar to that of the general population.

All but one of our patients had an unfavorable out-come. Apparently, these patients died of causes not directlyrelated to inv(9); for example, cases 2, 3, and 6 died ofsepsis within 4 weeks of diagnosis, case 4 died of livercirrhosis, and cases 5 and 6 died of recurrent leukemia.

Although recent reports of prolonged engraftment afterautologous and allogeneic transplantation of inv(9) donors[16,17] suggest an impaired engraftment potential of inv(9)hematopoietic stem cells, the hematopoietic recovery afterinduction chemotherapy in our series was not much differentfrom average of 25 to 29 days as reported in the literature[18,19]. It is possible that the hematopoietic defects of inv(9)manifest after repeated courses of chemotherapy, as in ourindex case. Alternatively the number of patients in our seriesmay be too small to discern a partial hematopoietic defectin patients with constitutional inv(9). Further studies arerequired to confirm our findings.

References

[1] Nielsen J, Wohlert M, Faaborg-Andersen J, Hansen KB, HvidmanL, Krag-Olsen B, Moulvad I, Videbech P. Incidence of chromosomeabnormalities in newborn children. Comparison between incidencesin 1969-1974 and 1980-1982 in the same area. Hum Genet 1982;61:98–101.

[2] Hansteen IL, Varslot K, Steen-Johnsen J, Langard S. Cytogeneticscreening of a new-born population. Clin Genet 1982;21:309–14.

[3] Hsu LY, Benn PA, Tannenbaum HL, Perlis TE, Carlson AD. Chromo-somal polymorphisms of 1, 9, 16, and Y in 4 major ethnic groups: alarge prenatal study. Am J Med Genet 1987;26:95–101.

[4] Tawn EJ, Earl R. The frequencies of constitutional chromosome abnor-malities in an apparently normal adult population. Mutat Res 1992;283:69–73.

[5] Keung YK, Knovic MA, Hurd DD, Pettenati M. Constitutional peri-centric inversion of chromosome 9 and bone marrow transplantation.Br J Haematol 2003 (in press).

[6] Ko TM, Hsieh FJ, Chang LS, Pan MF, Lee TY. Pericentric inversionsof chromosome 9 in Taiwanese fetuses. J Formos Med Assoc 1992;91:473–4.

[7] Uehara S, Akai Y, Takeyama Y, Takabayashi T, Okamura K, Yajima A.Pericentric inversion of chromosome 9 in prenatal diagnosis andinfertility. Tohoku J Exp Med 1992;166:417–27.

[8] Daya S. Issues in the etiology of recurrent spontaneous abortion. CurrOpin Obstet Gynecol 1994;6:153–9.

[9] Inayama Y, Yoneda H, Fukushima K, Sakai J, Asaba H, Sakai T.Paracentric inversion of chromosome 9 with schizoaffective disor-der. Clin Genet 1997;51:69–70.

Y.-K. Keung et al. / Cancer Genetics and Cytogenetics 145 (2003) 82–85 85

[10] Lee KB, Kunugi H, Nanko S. Familial schizophrenia with pericentricinversion of chromosome 9: a case report. Schizophr Res 1998;32:123–6.

[11] McCandless F, Jones I, Harper K, Craddock N. Intrafamilial associa-tion of pericentric inversion of chromosome 9, inv (9)(p11-q21), andrapid cycling bipolar disorder. Psychiatr Genet 1998;8:259–62.

[12] Miyazaki M, Hashimoto T, Tayama M, Kuroda Y, Ueta T. Congenitalmyotonic dystrophy associated with a chromosome pericentric inver-sion. Neuropediatrics 1991;22:181–3.

[13] Rege-Cambrin G, Kerim S, Scaravaglio P, Michaux JL, Van Den BergH, Saglio G. Chromosome abnormalities involving heterochromaticregions in monocytic leukemia. Cancer Genet Cytogenet 1990;46:99–106.

[14] Le Coniat M, Vecchione D, Bernheim A, Berger R. C-banding studiesin acute nonlymphocytic leukemia. Cancer Genet Cytogenet 1982;5:327–31.

[15] Petkovic I, Nakic M, Konja J. Heterochromatic variability in childrenwith acute lymphoblastic leukemia. Cancer Genet Cytogenet 1991;54:67–9.

[16] Keung YK, Pettenati MJ, Hurd DD, Powell BL, Buss DH. Allogeneicmarrow grafts from donors with congenital pericentric inversion ofchromosome 9. Br J Haematol 2002;116:238–9.

[17] Imashuku S, Naya M, An B, Nakabayashi Y, Kuriyama K, Udeda I,Morimoto A, Hibi S, Todo S. Constitutional pericentric inversion ofchromosome 9 and haemopoietic stem cell transplantation: delayedengraftment. Br J Haematol 2002;118:1195–6.

[18] Witz F, Sadoun A, Perrin MC, Berthou C, Briere J, Cahn JY, LioureB, Witz B, Francois S, Desablens B, Pignon B, Le Prise PY,Audhuy B, Caillot D, Casassus P, Delain M, Christian B, Tellier Z,Polin V, Hurteloup P, Harousseau JL. A placebo-controlled studyof recombinant human granulocyte-macrophage colony-stimulatingfactor administered during and after induction treatment for de novoacute myelogenous leukemia in elderly patients. Groupe Ouest EstLeucemies Aigues Myeloblastiques (GOELAM). Blood 1998;91:2722–30.

[19] Lowenberg B, Suciu S, Archimbaud E, Ossenkoppele G, Verhoef GE,Vellenga E, Wijermans P, Berneman Z, Dekker AW, Stryckmans P,Schouten H, Jehn U, Muus P, Sonneveld P, Dardenne M, Zittoun R. Useof recombinant GM-CSF during and after remission induction chemo-therapy in patients aged 61 years and older with acute myeloid leuke-mia: final report of AML-11, a phase III randomized study of theLeukemia Cooperative Group of European Organisation for theResearch and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group. Blood 1997;90:2952–61.