Cancer Genetics and Cytogenetics 142 (2003) 162–164

0165-4608/03/$ – see front matter © 2003 Elsevier Science Inc. All rights reserved.doi:10.1016/S0165-4608(02)00797-5

Letter to the editor

Novel constitutional t(2;12)(q21;q22) in a patient with t(9;22)-negative chronic myelocytic leukemia

We report a case of t(9;22)-negative chronic myelocyticleukemia (CML) with a novel constitutional t(2;12)(q21;q22).A 78-year-old female presented with a 6-month history offatigue, weakness, and occasional night sweats. Her medicalhistory revealed uterine polyposis at the age of 44, cervicalcancer diagnosed at the age of 55, and breast cancer diag-nosed at the age of 59. Three of five first-degree relativeshad died from malignant disorders. Specifically, her motherdied from cervical cancer at the age of 62, her father diedfrom a carcinoma of the gallbladder at the age of 52, and abrother died from colorectal cancer at the age of 84.

On admission, the patient’s spleen was enlarged to 16cm. Hematologic tests showed a hemoglobin level of 11.1g/dL, a platelet count of 471

�

10

9

/L, and a leukocyte countof 59

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10

9

/L with a differential count of 48% neutrophils,8% bands, 7% metamyelocytes, 16% myelocytes, 1% blasts,10% monocytes, and 10% lymphocytes. The bone marrowaspirate was hypercellular with 20% neutrophils, 16% bands,6% metamyelocytes, 18% myelocytes, 13% promyelocytes,1% monocytes, 4% eosinophils, 3% basophils, and 19%lymphocytes. Neutrophilic alkaline phosphatase in periph-eral blood granulocytes was negative.

Cytogenetic analysis of bone marrow cells showed a t(2;12)(q21;q22) as the sole aberration in all metaphases analyzed(Fig. 1). Dual-color fluorescence in situ hybridization withchromosome 2 and 12 specific probes confirmed this result(Fig. 2). No t(9;22)(q34;q11) could be detected. Multiplexreverse-transcriptase polymerase chain reaction failed to de-tect

BCR/ABL

mRNA transcripts in bone marrow cells.Subsequent karyotyping of fibroblasts from a skin biopsy ofthe patient and peripheral blood lymphocytes of her 44-year-old son without a history of neoplasia revealed thesame abnormality. Peripheral blood lymphocytes from threesons of the patient’s brother who had died from colorectalcancer showed a normal karyotype.

Whereas neither a somatic nor a constitutional t(2;12)(q21;q22) has been described in the literature, the break-point region 2q21 is known to be involved in chromosomaltranslocations with several partner chromosomes in diffuselarge B-cell lymphoma, follicular lymphoma, and squamouscarcinoma of the head and neck [1–7]. Cytogenetic aberra-tions including inversions and translocations of chromo-

somal region 12q22 have been found in acute and chronicmyelocytic leukemia, acute lymphoblastic leukemia, andchondroid hamartoma of the lung [8–12].

Interestingly, the kit ligand (

KL

; also known as stem cellfactor or steel factor) gene has been mapped to chromosomalregion 12q22 [13].

KL

is a hematopoietic cytokine that trig-gers its biologic effects by binding to its receptor c

-KIT

. Inaddition to their importance in physiologic processes, both

KL

and c

-KIT

play a role in the pathogenesis of certain hu-man tumors, including myeloproliferative disorders and gy-necologic neoplasias [13–15]. Whereas levels of soluble

KL

were within the normal range in our patient, the transmem-brane form was overexpressed as determined by immunoflu-orescence. Since imatinib (STI571) is a known inhibitor ofthe c-

ABL

,

BCR/ABL

,

PDGFR

, and c-

KIT

tyrosine kinases,we evaluated the effect of this compound on the proliferationof peripheral blood progenitor cells (PBPC) from our patientin vitro. Long-term exposure of t(2;12)(q21;q22)-positivePBPC lead to a 50% growth inhibition at a STI571 concentra-tion below 1

�

M, a finding equivalent to

BCR/ABL

-positivecolonies [16]. Furthermore, a growth-factor independent pro-liferation of t(2;12)(q21;q22)-positive PBPC was noted, sug-gesting an autocrine stimulation of the cells by the

KL

/c-

KIT

system. Therefore, we speculated that the chromosomal trans-location t(2;12)(q21;q22) might lead to overexpression of trans-membrane

KL

and thereby might play a role in the pathogen-esis of

BCR/ABL

-negative CML in our patient.Only 5 months from initial diagnosis the

BCR/ABL

-nega-tive CML progressed to accelerated phase with weight loss,severe night sweats, fever, hepatomegaly (15 cm), progres-sive splenomegaly (19 cm), anemia of 9.2 g/dL, thrombope-nia of 104

�

10

9

/L, and a leukocyte count of 102

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10

9

/Lwith 52% neutrophils, 11% bands, 3% metamyelocytes,12% myelocytes, 12% monocytes, and 10% lymphocytes.

Repeat cytogenetic analysis of bone marrow cells againshowed a t(2;12)(q21;q22) as the sole aberration in allmetaphases. Since imatinib inhibits c-

KIT

receptor tyrosinekinase activity and growth of human myeloid leukemia celllines [17] and has been reported to be effective in the treat-ment of gastrointestinal stromal tumors with activating c-

KIT

mutations [18], treatment with imatinib at a dose of 600 mgonce daily was initiated. Despite a reduction of leukocyte

Letter to the editor / Cancer Genetics and Cytogenetics 142 (2003) 162–164

163

numbers to 65

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10

9

/L the patient’s physical condition de-teriorated, so that imatinib treatment was stopped becauseof massive generalized edema 2 weeks after initiation. Shefailed to respond to subsequent treatment attempts with hy-droxyurea and cytosine arabinoside and died 4 weeks later.

We conclude that the balanced constitutional t(2;12)(q21;q22) in the patient described here might be related tothe development of her t(9;22)-CML and her gynecologicmalignancies, possibly via overexpression of

KL

.

Alwin KrämerStefan FruehaufAnthony D. Ho

Medizinische Klinik und Poliklinik VUniversität Heidelberg

Heidelberg, Germany

Hans-Dieter HagerClaus R. Bartram

Institut für HumangenetikUniversität Heidelberg

Heidelberg, Germany

Andreas Hochhaus

Medizinische Klinik Mannheim IIIUniversität Heidelberg

Mannheim, Germany

References

[1] Jin Y, Higashi K, Mandahl N, Heim S, Wennerberg J, Biörklund A,Dictor M, Mitelman F. Frequent rearrangement of chromosomalbands 1p22 and 11q13 in squamous cell carcinomas of the head andneck. Genes Chromosomes Cancer 1990;2:198–204.

[2] Koduru PRK, Filippa DA, Richardson ME, Jhanwar SC, ChagantiSR, Koziner B, Clarkson BD, Lieberman PH, Chaganti RSK. Cytoge-netic and histologic correlations in malignant lymphoma. Blood1987;69:97–102.

[3] Maseki N, Kaneko Y, Sakurai M, Kurihara M, Sampi K, ShimamuraK, Takayama S. Chromosome abnormalities in malignant lymphomain patients from Saitama. Cancer Res 1987;47:6767–75.

[4] Peters K, Zettl A, Starostik P, Greiner A, Rosenwald A, KatzenbergerT, Ott G, Müller-Hermelink HK. Genetic imbalances in primary gas-tric diffuse large B-cell lymphomas: comparison of comparative ge-

Fig. 1. The t(2;12)(q21;q22) as observed in all metaphases from bone marrow cells and cultured skin fibroblasts of the patient.

Fig. 2. Dual-color fluorescence in situ hybridization of a metaphase frombone marrow. The patient’s chromosomes 2 and 12 are stained in red andgreen, respectively.

164

Letter to the editor / Cancer Genetics and Cytogenetics 142 (2003) 162–164

nomic hybridization, microsatellite, and cytogenetic analysis. DiagnMol Pathol 2000;9:58–65.

[5] Bloomfield CD, Arthur DC, Frizzera G, Levine EG, Peterson BA,Gajl-Peczalska KJ. Nonrandom chromosome abnormalities in lym-phoma. Cancer Res 1983;43:2975–84.

[6] Chen W, Butler M, Rao PH, Chaganti SR, Louie DC, Dalla-Favera R,Chaganti RSK. The t(2;3)(q21;q27) translocation in non-Hodgkin’slymphoma displays BCL6 mutations in the 5

�

regulatory region andchromosomal breakpoints distant from the gene. Oncogene 1998;17:1717–22.

[7] Konishi H, Sakurai M, Nakao H, Maseki N, Kaneko Y, Yagiri Y, No-tohara K, Frizzera G. Chromosome abnormalities in malignant lym-phoma in patients from Kurashiki: histological and immunopheno-typic correlations. Cancer Res 1990;50:2698–703.

[8] Raimondi SC, Shurtleff SA, Downing JR, Rubnitz J, Mathew S, Han-cock M, Pui C-H, Rivera GK, Grosveld GC, Behm FG. 12p abnor-malities and the TEL gene (ETV6) in childhood acute lymphoblasticleukemia. Blood 1997;90:4559–66.

[9] Kazmierczak B, Meyer-Bolte K, Tran KH, Wöckel W, Breightman I,Rosigkeit J, Bartnitzke S, Bullerdiek J. A high frequency of tumorswith rearrangements of genes of the HMGI(Y) family in a series of191 pulmonary chondroid hamartomas. Genes Chromosomes Cancer1999;26:125–33.

[10] Thurston VC, Ceperich TM, Vance GH, Heerema NA. Detection ofmonosomy 7 in bone marrow by fluorescence in situ hybridization. Astudy of Fanconi anemia patients and review of the literature. CancerGenet Cytogenet 1999;109:154–60.

[11] Kadam PR, Merchant AA, Advani SH. Cytogenetic findings in pa-

tients with acute promyelocytic leukemia and a case of CML blastcrisis with promyelocytic proliferation. Cancer Genet Cytogenet1990;50:109–17.

[12] Koo SH, Kwon GC, Chun HJ, Park JW. Cytogenetic and fluores-cence in situ hybridization analyses of hematologic malignancies inKorea. Cancer Genet Cytogenet 1998;101:1–6.

[13] Broudy VC. Stem cell factor and hematopoiesis. Blood 1997;90:1345–64.

[14] Moore S, Haylock DN, Lévesque J-P, McDiarmid LA, Samels LM,To LB, Simmons PJ, Hughes TP. Stem cell factor as a single agent in-duces selective proliferation of the Philadelphia chromosome positivefraction of chronic myeloid leukemia CD34

�

cells. Blood 1998;92:2461–70.

[15] Inoue M, Kyo S, Fujita M, Enomoto T, Kondoh G. Coexpression ofthe c-kit receptor and the stem cell factor in gynecological tumors.Cancer Res 1994;54:3049–53.

[16] Topaly J, Fruehauf S, Ho AD, Zeller WJ. Rationale for combinationtherapy of chronic myelogenous leukaemia with imatinib and irradia-tion or alkylating agents: implications for pretransplant conditioning.Br J Cancer 2002;86:1487–93.

[17] Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ.Inhibition of c-kit receptor tyrosine kinase activity by STI571, a se-lective tyrosine kinase inhibitor. Blood 2000;96:925–32.

[18] Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahar-tiala P, Tuveson D, Silberman SL, Capdeville R, Dimitrijevic S,Druker B, Demetri GD. Effect of the tyrosine kinase inhibitor STI571in a patient with a metastatic gastrointestinal stromal tumor. N Engl JMed 2001;344:1052–6.