Cancer Investigation, 27:718–722, 2009ISSN: 0735-7907 print / 1532-4192 onlineCopyright c© Informa Healthcare USA, Inc.DOI: 10.1080/07357900802653498

ORIGINAL ARTICLECellular and Molecular Biology

t(3;9;22) 3-Way Chromosome Translocation inChronic Myeloid Leukemia is Associated with

Poor PrognosisJiahuai Tan,1 Shundong Cang,2 Karen Seiter,2 Suneeta Primanneni,2 Nasir Ahmed,1 Thomas Mathews,3

and Delong Liu2

Department of Medicine, Mount Vernon Hospital, Mount Vernon, New York, USA.1

Division of Oncology/Hematology, New York Medical College and Westchester Medical Center, New York, USA.2

Department of Pathology, New York Medical College and Westchester Medical Center, New York, USA.3

ABSTRACT

Chronic myelogenous leukemia (CML) is genetically characterized by the reciprocal translo-cation of chromosome 9 and 22. Around 5–8% of CML develop complex variant Ph translo-cations involving one or more chromosomal regions besides 9 and 22. Chromosome 3 is notfrequently involved in complex translocations in CML. We report in this study a case of CMLdisplaying a t(3;9;22) 3-way translocation. A review of the literature appears to indicate thatCML patients with this translocation tend to have an aggressive course and poor outcome.Additional 3-way chromosome translocations associated with CML are also reviewed.

INTRODUCTION

Chronic myelogenous leukemia (CML) is genetically char-acterized by the reciprocal translocation of chromosome 9 and22 (1), which results in the fusion of BCR-ABL gene on thePhiladelphia chromosome (Ph+) (2). An abnormal BCR-ABLtyrosine kinase protein is produced from the fused gene andplays a pathogenetic role in CML leukemogenesis and clinicalcourse (3). Imatinib mesylate is a selective inhibitor of BCR-ABL kinase and induces major cytogenetic remission in 83% ofnewly diagnosed cases with the common t(9;22) (4).

Around 5–8% of CML develop complex variant transloca-tions involving one or more chromosomal regions besides 9 and22 (5). These abnormalities are clearly nonrandom, with themost common chromosomal aberrations involving trisomy 8,19, more than one copy of Ph+, and isochromosome 17q. Mon-

Keywords: Chronic myelogenous Leukemia, Cancer genetics,Chromosomal t(3;9;22), 3-way translocationCorrespondence to:Delong Liu, MD, PhD, Associate Professor of MedicineDivision of Oncology and HematologyNew York Medical College and Westchester Medical CenterMunger Pavilion 250, Valhalla, NY 10595, USAemail: delong liu@nymc.edu

somy 7, 17, loss of Y chromosome, and trisomy 17 and 21 areless frequent (6). The evolution of CML in the presence of extraabnormalities and the prognostic significance of the additionalgenetic changes in Ph+ patients have not been fully understoodmainly due to limited number of variant CML patients (7).

Chromosome 3 is not frequently involved in complex translo-cations and was reported as a negative prognostic factor recently(8). We report in this study a case of CML displaying an un-common t(3;9;22) 3-way translocation. A review of the literatureappears to indicate that patients with this translocation tend tohave an aggressive course.

CASE REPORT

The patient was a 62-year-old male with history of coronaryartery disease with bypass, diabetes mellitus, and hypertension.He presented with a white count of 25,000 in May 2007. He hadno splenomegaly. The bone marrow evaluation revealed blastsless than 5%. Chromosome study of the bone marrow spec-imen revealed a 3-way translocation, t(3;9;22) (p21;q34;q11)(see Figure 1). The patient was diagnosed to have CML inchronic phase. He was started on Imatinib 400 mg daily. Thepatient achieved complete hematological remission. In Febru-ary 2008, he complained of visual disturbance. It was attributedto the side effects of Imatinib, which was held for 2 weeks.The patient was later admitted to a local hospital for pneumonia

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Figure 1. Karyotype of a CML patient with t(3;9;22) 3-way chromosome translocation. Arrows indicate the chromosomes involved in the 3-waytranslocation. An additional X chromosome was also indicated.

and found to have pancytopenia. Five days later, he was trans-ferred to the Westchester Medical Center (WMC) for furthermanagement of leukemia. Physical examination revealed lym-phadenopathy in left subclavian area with an enlarged spleen.On admission, the peripheral white blood cell count (WBC) was1000/cu mm. The hemoglobin (Hb) was 9.6 g/dl and plateletcount was 22000/cu mm. Flow cytometry analysis of the bonemorrow sample showed an immature B cell population (52%

of total) expressing CD19, CD20, CD22, CD10, CD34, CD38,and Tdt, which are consistent with bone marrow involvementby precursor B-cell acute lymphoblastic leukemia (precursorB-ALL). Chromosome study revealed 47, XY, +X, t(3;9;22)(p21;q34;q11.2). FLT3 mutation tests were also done in this pa-tient. BCR-ABL gene mutation analysis was requested but testwas not done due to lab error. The cytology report from cere-brospinal fluid showed an increased number of lymphocytes

Table 1. Cases of CML with t(3;9;22) Chromosome Translocation

Stage ofCML at

Karyotype/Reference Presentation Treatment Outcome

t(3;9;22)(p21;q34;q11) (1) Not reported Not reported Not reportedt(3;9;22)(q21;q32;q11) (8) Chronic phase Interferon-alfa (IFN) Complete hematologic response (CHR) for

1 year, then progressed to a blasticphase and died a few weeks later

t(3;9;22)(q21;q32;q11) (8) Chronic phase Hydroxyurea for 1 year, then Imatinib 400mg/day for 1 year, then Bone marrowtransplantation (BMT) with high-dosethiotepa, busulfan andcyclophosphamide as preparativeregimen

No cytogenetic response was achieved onImatinib. Only achieved completeremission after BMT

t(3;9;22)(p25;q34;q11) (15) Chronic phase Hydroxyurea Remained stable for 9 monthst(3;9;22)(p21;q34;q11)and inv(3) (21) Blastic crisis Hydroxyurea Died from this disease in 3 montht(3;9;22)(q21;q34;q11) (22) Chronic phase Mylecytan (busulfan) for 4 years then

changed to hydroxyureaOnly partial hematological remission. Died

from internal bleeding from rupture ofthe gastric ulcer 4 years after diagnosis

t(3;9;22)(p22;q34;q12) (23) Not reported Not reported Not reportedt (3;9;22)(q24;q34;q11) (24) Not reported Not reported Not reportedt(3;9;22)(p21;q32;q11) [this report] Chronic phase Imatinib for 8 months, then hyper-CVAD +

dasatinib induction at blast crisisLymphoid blast crisis 8 months after

diagnosis, died during induction

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Table 2. CML with Complex Chromosome Translocations

Stage ofCML at

Karyotype/Reference Presentation Treatment Outcome

t(3;9;17;22) (25) Blast crisis Imatinib No responset(4; 9; 22) (26) Chronic phase Hydroxyurea Stable for 3 yearst(4;9;22)(p16;q34;q11) (27) Chronic phase Hydroxyurea 1 year to blast crisis (BC)t(4;12;7;9;22) (28) Chronic phase Imatinib Complete Remission (CR) at 41

monthst(5;9;22) (29) Chronic phase Busulfan/Interferon-alfa (IFN) 3 years to BCt(5;9;22) (30) Not Reported (NR) NR NRt(5;9;22)(q13;q34;q11) (31) NR NR NRt(5;9;22)(q31;q34;q11) (32) NR NR NRt(6;9;12;22)(p21;q34;q24;q11) (33) NR NR NRt(8;9;22) (q22;q34;q11) (32) NR NR NRt(9;22;9;11) (q34;q11;p22;q23) (34) Chronic phase Hydroxyurea Stable for 18 monthst(9;22;11) (35) Chronic phase Imatinib Hematological Remission (HR) at 1

yeart(9;22;11) (q34;q11;q13) (36) NR NR NRt(9;22;12)(q34;q11;q11) (37) NR NR NRt(9;15;22)(q34;q22;q11) (33) NR NR NRt(9;15;22) (q34;q15;q11) (32) NR NR NRt(9;22;16)(q34;q11.2;p13 (38) Chronic phase Imatinib HR at 7 monthst(9;22;17) (39) Chronic phase Hydroxyurea/Bone marrow

transplantation (BMT)10 months to BC

t(9;18;22)(q34;p11;q11) (40) Chronic phase Hydroxyurea No responset(9;22;21;11;inv ins(12)-(q15p12p13)) (41) Blast crisis Vincristine and Prednisolone Died in 2 yearst(Y;9;22)(q12;q34;q11) (42) Chronic phase Hydroxyurea 3 months to Accelerated Phase

(AP)

suspicious for CNS involvement by leukemia. Hyper-CVADchemotherapy together with rituximab and dasatinib was givenas induction chemotherapy [(9, 10). Intrathecal methotrexatewas given for CNS leukemia involvement. Patient died of septicshock 2 weeks later in neutropenic nadir.

DISCUSSION

This CML patient was presented with t(3;9;22) 3-waytranslocation and evolved into lymphoid blast crisis only 8months after initial diagnosis while on Imatinib therapy. There-fore the patient developed Imatinib resistance fairly rapidly.

There are several mechanisms for CML resistance to Ima-tinib treatment, which include amplification or copy numberincrease of the BCR-ABL fusion gene, mutation in BCR-ABLenzyme domain, or other tyrosine kinase activation(FLT3 mu-tation) (11). Of the proposed mechanisms, a major cause ofImatinib resistance for patients with CML is clonal evolutionof leukemic cells with mutations in the BCR-ABL tyrosine ki-nase. These mutations have been detected over a range of 242amino acids, which span the entire kinase domain (12–14). It isunfortunate that BCR-ABL mutation analysis was not done dueto a lab error. The frequency of BCR-ABL mutations increasesin accelerated phase and blast crisis as well as with diseaseduration (14). Therefore patients with CML in these phasestend to develop Imatinib-resistant mutations. Selection of resis-tant clones during therapy and clonal cytogenetic evolution withlonger duration of CML may be responsible for the developmentand expansion of the resistant clones with the mutations. This

patient was presented with a de novo 3-way translocation, andhad no new cytogenetic abnormality at blast crisis. Therefore,Imatinib-refractory mutation(s) is the most likely mechanismresponsible for the disease progression to blast crisis.

Chromosome 3 has been reported to be part of variant Phtranslocations in 35 cases, with the short arm 3p21 breakpointsbeing most common (15). The proto-oncogene c-raf-1 has beenmapped to the 3p region (15). Tumor suppressor genes suchas H37/Luca15/RBM5 and RASSFIA and tumor susceptibil-ity genes (hMLH1) have been identified in chromosome 3p21region (16–19). Deletion or translocation involving this regionhas also been reported to be associated with acute leukemia andmyelodysplastic syndrome, human epithelial malignancies, in-cluding small cell lung and renal cell carcinomas (16–20). Over-expression of the tumor suppressor gene, H37/Luca15/RBM5,resulted in cell cycle arrest and apoptosis in human lung carci-noma, indicating that the genes in the 3p21 region play a criticalrole in tumorigenesis (16).

A literature search through Pubmed showed that a total ofnine patients were reported to have t(3;9;22) (1, 8, 15, 21–24) (Table 1). Three out of nine patients had only reportedkaryotype studies (1, 23, 24). One out of nine patients onhydoxyurea had only a 9-month follow-up (15). For the restfive patients, four were diagnosed in the chronic phase andone in the blastic crisis phase (Table 1). Although the precisebreakpoint at 3p21 and the genes involved in this t(3;9;22)3-way translocation have not been clearly defined, it appearsthat the patients with this 3-way translocation at presentationhad worse outcome, including the two who had Imatinib, but

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did not achieve good cytogenetic response. The only durablecomplete remission was achieved from myeloablative bonemarrow transplantation (8). Therefore it seems reasonable tohave frequent monitoring of patient-response status. For subop-timal responders, second-line tyrosine kinase inhibitors, such asdasatinib and nilotinib, may be considered (14). It is not clearwhether hematopoietic stem cell transplantation should be con-sidered early in CML patients with this 3-way translocation atpresentation.

Additional complex chromosome translocations have alsobeen reported as case reports or small series in CML patients(25–42) (Table 2). Chromosomes 3, 4, 5, 6, 8, 11, 12, 15, 16,17, 18, 21, and Y have been reported in 3-way, 4-way, or 5-waytranslocations in CML patients (Table 2). Most of these reportsfocused on cytogenetic abnormalities and gave very sketchydata on patients’ disease status. Most patients received hydrox-yurea, busulfan, or interferon. Four cases were given Imatinib;one of them with 4-way translocations had no response (25).Molecular study of the breakpoints in this patient revealed ac-tivation of a second oncogene, EV11 (25). Further clinical andmolecular studies on these complex translocations are neededto improve therapeutic outcome of CML patients with complexchromosome abnormalities.

ACKNOWLEDGMENTS

We thank the cytogenetics laboratory at the Westchester Med-ical Center for the excellent technical support.

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