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Chronic Myelomonocytic Leukemia with Der(9)T(1;9)(Q11;Q34) As a Sole Abnormality

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Chronic Myelomonocytic Leukemia with Der(9)T(1;9)(Q11;Q34) As a Sole Abnormality Available online at www.annclinlabsci.org Annals of Clinical & Laboratory Science, vol. 39, no. 3, 2009 307 Case Report and Review of the Literature: Chronic Myelomonocytic Leukemia with der(9)t(1;9)(q11;q34) as a Sole Abnormality Borum Suh,1 Tae Sung Park,1* Jin Seok Kim,2 Jaewoo Song,1 Juwon Kim,1 Jong-Ha Yoo,1,3 and Jong Rak Choi1 Departments of 1Laboratory Medicine and 2Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; 3Department of Laboratory Medicine, National Health Insurance Corporation Ilsan Hospital, Goyang-si, Kyonggi-do, Korea Abstract. The chromosomal abnormality der(9)t(1;9)(q11;q34) is a rare occurrence in patients with hematologic malignancies. As far as we know, only 3 cases of acute myeloid leukemia, 1 case of polycythemia vera, and 1 case of multiple myeloma with this derivative chromosome have been reported in the literature. Here we report the first case of der(9)t(1;9)(q11;q34) in a patient with chronic myelomonocytic leukemia (CMML). A 45-yr-old man was brought to our hospital for evaluation of pancytopenia and monocytosis. The patient’s persistent monocytosis in peripheral blood and his bone marrow findings were consistent with the diagnosis of CMML. Chromosome study results repeatedly showed 46,XY,der(9)t(1;9)(q11;q34). In addition, the BCR/ABL fluorescent in situ hybridization (FISH) pattern of the interphase cells was interpreted as: “nuc ish(ABL, BCR) x 2[292/300],” consistent with the normal signal patterns found in 97% of the nuclei examined. For further evaluation, multi-color FISH (mFISH) analysis was performed and it showed the distinct unbalanced derivative chromosome der(9)t(1;9)(q11;q34) in 5 metaphase cells analyzed. Not only does this show an extraordinary type of trisomy 1q, but it reveals a rare recurrent case of der(9)t(1;9)(q11;q34) in patients with monocytic-lineage leukemia. Further studies are needed to evaluate the prognosis, survival, and treatment response of such patients with der(9)t(1;9)(q11;q34). Keywords: der(9)t(1;9)(q11;q34), CMML, mFISH, monocytic-lineage leukemia Introduction myeloproliferative neoplasm (MPN) by the presence of both dysplastic and proliferative features at the Chronic myelomonocytic leukemia (CMML) is a time of initial presentation [1,2]. The most common clonal disorder of bone marrow stem cells in which chromosomal abnormalities in MDS or CMML monocytosis is a major defining feature [1]. CMML are deletion 5q, monosomy 7, and trisomy 8. was initially classified in the category of myelodys- Although a predominance of trisomy 1q in Korean plastic syndrome (MDS), but it is now categorized patients with MDS has been reported [3], complete by the 2001 World Health Organization (WHO) trisomy 1q is rare, even in Korean CMML patients. classification in a separate nosological group of In addition, der(9)t(1;9)(q11;q34) has been reported MDS/MPN, which is distinguished from MDS or in only 5 patients, including a case of acute myelomonocytic leukemia (AML-M4), a case of * Dr Tae Sung Park’s current address is Department of Laboratory Medicine, Kyung Hee Univiversity Medical acute monocytic leukemia (AML-M5a), and an School, Seoul, Korea; tel 822 958 8673; fax 822 958 8609. unspecified AML with myeloid sarcoma, but not in Address correspondence to: Jong Rak Choi, M.D., Ph.D., CMML patients [4-9]. We describe a novel case of Department of Laboratory Medicine, Yonsei University der(9)t(1;9)(q11;q34) in a patient with CMML, College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea; tel 822 2228 2445; fax 822 313 0956; e-mail and review the medical and laboratory data of the [email protected]. patient and the relevant literature. 0091-7370/09/0300-0307. $2.10. © 2009 by the Association of Clinical Scientists, Inc. 308 Annals of Clinical & Laboratory Science, vol. 39, no. 3, 2009 Case Report Upon arrival, his CBC showed a Hb level of 9.0 g/dl, a platelet count of 130,000 /μl, and a WBC count of 2,090 /μl, with A 45-year old Korean man with a history of diabetes mellitus 14% segmental neutrophils, 21% lymphocytes, 3% atypical dating from November 2002 was brought to Ilsan Hospital lymphocytes, 2% immature cells, and 60% monocytes. His for evaluation of pancytopenia in August 2004. Complete third bone marrow examination, May 2008, showed normo- blood count (CBC) showed a hemoglobin (Hb) level of 8.5 cellularity with 3.3% blasts. Peripheral blood monocytosis g/dl, a platelet count of 120,000/μl, and a WBC count of (>1,000 /μl) has been consistently observed after the initial 1,900 /μl. Pancytopenia compelled us to perform a peripheral diagnosis of CMML. For further evaluation, cytogenetics, blood smear (PBS) and bone marrow examination, and the fluorescent in situ hybridization (FISH), and multi-color WBC differential counts were as follows: 24% segmental FISH (mFISH) analyses were conducted. neutrophils, 31% lymphocytes, and 45% monocytes. The first bone marrow aspiration (August 2004) showed 80% hyper- Materials and Methods cellular marrow with erythroid hyperplasia (the myeloid to erythroid ratio was 1.1:1). Although dyspoietic megakaryo- Standard cytogenetic techniques and nomenclature were cytes (microforms, separated nuclear lobules) were detected, followed [10]. no other distinct dysplasia was observed in the marrow. The FISH analysis was performed according to the PBS and bone marrow findings were consistent with the manufacturer’s instructions with commercially available diagnosis of CMML. FISH probes supplied by Abbott Molecular/Vysis (Des The patient was referred to Severance Hospital in March Plaines, IL). The analyses were performed with probes for 2005. His second bone marrow aspiration, July 2005, showed BCR/ABL (LSI BCR/ABL Dual Color, Dual Fusion a moderately hypercellular marrow with marked increase of Translocation Probe Set), IGH/MYC (LSI IGH(14q32)/ abnormal megakaryocytes. He was treated with oxymetholone MYC(8q24), CEP 8 Tri-Color, Dual Fusion Translocation for anemia on an outpatient basis, and was admitted to Probe Set), p53 (LSI 17p13.1 SpectrumOrange Probe), and Severance Hospital for decitabin treatment in May 2008. probes for chromosome 5 (LSI EGR1 (5q31) SpectrumOrange/ Fig. 1. (a) A metaphase cell stained with Giemsa-banding before analysis. (b) Full karyogram of the bone marrow cells: 46,XY, der(9)t(1;9)(q11;q34). (c) Partial karyogram of der(9)t(1;9)(q11;q34) in this patient. (d) Diagrammatic representation of chromosome 9 and der(9)t(1;9)(q11;q34). The arrows indicate breakpoints of chromosomes 1 and 9. A case of CMML with der(9)t(1;9)(q11;q34) 309 Fig. 2. Results of multi-color FISH (mFISH) analysis in this patient. (a) A metaphase cell stained with the human 24XCyte probe before analysis. (b) mFISH image (false color labeled) showing der(9)t(1;9)(q11;q34) as the sole abnormality. The arrows indicate der(9)t(1;9)(q11;q34). (c) Parital image of inverted DAPI showing der(9)t(1;9)(q11;q34). (d) Single color galleries showing normal chromosome 1, normal chromosome 9, and der(9)t(1;9)(q11;q34), respectively. D5S23,D5S721 SpectrumGreen Probe Set), chromosome 7 studies were as follows: 46,XY,der(9)t(1;9)(q11;q3) (LSI D7S486 (7q31) SpectrumOrange/CEP 7 SpectrumGreen in 20 cells (August 2004), 14 cells (July 2005), and Probe Set), and chromosome 20 (LSI D20S108 (20q12) SpectrumOrange Probe). At least 300 bone marrow interphase 22 cells (May 2008) (Fig. 1). FISH signals from the cells were scored for signal patterns for each probe using a BCR/ABL probe showed the normal signal pattern fluorescence microscope (Axio Imager M1; Carl Zeiss Micro- in 97% of the nuclei examined, which was Imaging GmbH, Germany). interpreted as “nuc ish(ABL, BCR) x 2[292/300].” The mFISH analysis was performed with a human This is consistent with the karyotyping analysis, in 24XCyte (MetaSystems, Altlussheim, Germany) probe. The hybridization, post-hybridization washes, and signal detection which t(9;22)(q34;q11.2) was not detected, and were carried out according to the manufacturer’s protocol excludes the possibility of ABL gene involvement. (http://www.metasystems.de/downloads/mfish-manual.pdf). The results of the other FISH analyses with the Images were analyzed, captured, and processed with a IGH/MYC, p53, chromosome 5, chromosome 7, fluorescence microscope (Carl Zeiss MicroImaging GmbH) and Isis/mFISH imaging software (MetaSystems). and chromosome 20 probes were within reference ranges. In addition, mFISH analysis revealed the Results distinct unbalanced derivative chromosome der(9)t(1;9)(q11;q34) in 5 metaphase cells (May The patient repeatedly exhibited the same chromo- 2008) (Fig. 2), consistent with the cytogenetic somal abnormality. The results of the chromosome results of this patient (Fig. 1). 310 Table 1. Comparison of previous reports with der(9)t(1;9)(q11;q34) and this study. Annals Clinical of &Laboratory Science, vol. no. 3, 39, 2009 Case 1 Case 2 Case 3 Sex/Age M/45 (yr) F/56 (yr) F/21 (mo) Diagnosis CMML AML-M4 AML-M5a Abnormal karyotype 46,XY,der(9)t(1;9)(q11;q34) 46,XX,der(9)t(1;9)(q11;q34) 46,XX,t(1;9)(q11;q34)/46,idem, ins(10;11)(p12;q23q13) N of analyzed cells (abnormal/total) 56/56 14/28 NA Peripheral blood Initial WBC counts (/μl) 1,900 44,700 11,700 Dominant cells (%) 45 (monocytes) 19 (myelocytic precursors) 37 (monoblasts) Initial BM findings 80% hypercellular marrow with erythroid Hypercellular marrow 100% of leukemic cells hyperplasia, dyspoietic megakaryocytes with 40% of leukemic cells FISH (or further study) No BCR/ABL rearrangement (mFISH) ABL was not involved NA Treatment oxymetholone, decitabin fludarabine, cytarabine, idarubicine r ubidazone, cytarabine, teniposide Follow up 4 yr NA >6 mo (CR status) (no CR) (CR after one course of chemotherapy) (CR) References Park et al, 2009 [present study] Piccaluga et al, 2004 [5] Berger et al, 1982 [6] Abbreviations: M, male; F, female; CMML, chronic myelomonocytic leukemia; AML-M4, acute myelomonocytic leukemia; AML-M5a, acute monoblastic leukemia (poorly differentiated); BM, bone marrow; NA, not available; FISH, fluorescence in situ hybridization; mFISH, multi-color FISH; CR, complete remission.
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