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Biphenotypic acute leukemia with b2a2 fusion transcript and trisomy 21

Biphenotypic acute leukemia with b2a2 fusion transcript and trisomy 21
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  Letter to the editor Biphenotypic acute leukemia with b2a2 fusion transcript and trisomy 21 Biphenotypic acute leukemia (BAL) is a rare leukemia,which is identified in 5-10 % of acute leukemia (AL) cases.BAL has been described in the literature as mixed lineageor hybrid AL, myeloid antigen-positive acute lymphoblas-tic leukemia (ALL), and lymphoid antigen-positive acutemyeloid leukemia (AML) [1,2]. The European Group forImmunological Classification of AL (EGIL) has proposedguidelines for scoring lineage-specific antigens commonlyused to assign cell lineage [3]. To our knowledge, there isno single chromosomal abnormality which is uniquely as-sociated with BAL. However, several reports revealed thatthere was a high incidence of the Philadelphia chromo-some, t(9;22), in BAL cases [1,4 e 6], although most of the reported cases were associated with minor  BCR/ABL1 rearrangement. To our knowledge, only 2 cases of b2a2and one case of b3a2 have been documented in BAL[1,7]. In this report, we describe a rare case of BAL withb2a2 fusion transcript accompanying trisomy 21 showingcharacteristic laboratory findings and clinical features.A 68-year old female was brought to Severance Hospitalof Yonsei University with general weakness and poor oralintake. An initial complete blood count (CBC) showed a he-moglobin (Hb) level of 9.4 g/dL, a platelet count of 182,000/  m L, and a WBC count of 311,700/  m L with 13%segmental neutrophils, 7% lymphocytes, 1% monocytes,3% atypical lymphocytes, 4% eosinophils, 1% band forms,7% myelocytes, 2% promyelocytes, and 62% immaturecells. Bone marrow aspiration showed a hypercellular mar-row packed with leukemic cells, and biopsy confirmedpacked marrow showing diffuse proliferation of immatureblastic cells. Flow cytometry analysis showed the blaststo be positive for CD10 (43.7%), CD13 (86.1%), CD19(67.4%), CD33 (74.7%), CD45 (80.2%), CD79a (74.4%),and MPO, and negative for CD3 (2.9%), CD7 (0.2%),CD14 (5.2%), CD20 (1%), cCD22 (0.8%), CD117(0.4%), and TdT.Chromosome study showed a 47,XX,t(9;22)(q34;q11.2), þ 21 chromosome complement in all 20 metaphasecells analyzed (Fig. 1). Multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) assay was performedwith HemaVision TM kit (Bio-Rad Laboratories, Hercules,CA), which is designed to detect 28 kinds of fusion tran-scripts. The result of gene rearrangement test was consis-tent with the chromosome study showing b2a2 fusiontranscript (Fig. 2). The FISH analysis of BCR/ABL1 alsoshowed a result of ‘‘nuc ish(ABL1x3),(BCRx3),(ABL1con BCRx2)[132/157]’’. After being diagnosed with BALin association with hyperleukocytosis, she underwent leu-kapheresis 3 times. Subsequently, decision was made forher to be discharged from our hospital and referred to an-other regional institution.Three distinct breakpoint cluster regions (BCRs) in theBCR genome have been described in the  BCR/ABL1  rear-rangement [8]: m-  BCR  (minor type) corresponding to the  BCR  first intron, M-  BCR  (major type) spanning  BCR  exons12 to 16 (alternatively designed b1 to b5, respectively), and m -  BCR  (micro type) encompassing  BCR  exons 17 to 20 (c1to c4, respectively).Although BAL is not associated with a specific molecularor cytogenetic abnormality, about a third of BAL cases havethe  BCR/ABL1  rearrangement or Philadelphia chromosome.These cases usually have both a CD10 þ  precursor B lym-phoid component and a minor type (e1a2) of   BCR/ABL1  fu-sion transcript [1,4,7,9]. As mentioned above, only a fewcases of BAL with a major (b2a2, b3a2)  BCR/ABL1  rear-rangement have been reported in the literature (Table 1).The high incidence of childhood leukemia in childrenwith Down syndrome (DS) strongly suggests that the addi-tional copies of chromosome 21 are leukemogenic [10]. Inaddition, acquired trisomy 21 is a rare karyotypic abnor-mality detected in 0.4% of human neoplasms without Downsyndrome (DS), and only one case of BAL with trisomy 21has been reported as a sole abnormality [11]. Although Fig. 1. G-banded karyogram of bone marrow cells: 47,XX,t(9;22)(q34;q11.2), þ 21.0165-4608/09/$  e  see front matter    2009 Elsevier Inc. All rights reserved.doi:10.1016/j.cancergencyto.2008.10.008Cancer Genetics and Cytogenetics 188 (2009) 129 e 131  constitutional abnormality such as DS was not completelyruled out in our patient, we considered that trisomy 21 inthis study was more likely an acquired abnormality relatedto BAL on the basis of clinical history and age of our pa-tient. To the best of our knowledge, this is the first reportof BAL in association with b2a2 fusion transcript accompa-nying trisomy 21. Further studies are needed to evaluate thetreatment response and survival of such a BAL patient.Tae Sung Park   Department of Laboratory MedicineYonsei University College of Medicine 250 Seongsanno, Seodaemun-gu,Seoul 120-752, Korea Seung Tae Lee  Department of Internal MedicineYonsei University College of Medicine 250 Seongsanno, Seodaemun-gu,Seoul 120-752, Korea Jaewoo SongKyung-A. LeeJuwon KimYongjung Park Sungwook SongJong Rak Choi  Department of Laboratory MedicineYonsei University College of Medicine 250 Seongsanno, Seodaemun-gu,Seoul 120-752, Korea E-mail address:  cjr0606@yuhs.ac  (J.R. Choi) References [1] Legrand O, Perrot JY, Simonin G, Baudard M, Cadiou M, Blanc C,Ramond S, Viguie´ F, Marie JP, Zittoun R. Adult biphenotypic acuteFig. 2.  (a)  Master polymerase chain reaction (PCR) with Hemavision kit (BioRad Laboratories, CA) showed bands with 397 bp in lane 6 and 1700 bp in lane8 in addition to the internal control band of size 911 bp in each lane.  (b)  Split-out PCR results for lane 6 showed the same size (397 bp) band in lane 6B withthe internal control band of size 911 bp in each lane. A split-out PCR result revealed that PCR product of this patient was a b2a2 type of   BCR/ABL1  fusiontranscript. The result of lane 8 (master PCR) was regarded as invalid data according to the provided manual of Hemavision kit. Lane M, DNA of 100-bpladder as a size marker; lanes 1-8, master PCR lanes (screening); lanes 6A-6E, split-out PCR lanes.Table 1Summary of biphenotypic acute leukemia (BAL) patients with major  BCR/ABL1  rearrangements in the literaturePositive markers for immunophenotyesCaseno. Sex AgeFABsubtypes Karyotype B-lymphoid T-lymphoid Myeloid  BCR/ABL  fusiontranscript References1 F 64 M0 46,XX,t(9;22)(q34;q11)[23] CD10,CD19,CD22,TdTNone CD13,CD33,MPO b2a2 [1]2 F 43 M1 46,XX,t(9;22)(q34;q11)[34] TdT CD2,CD5,CD7 CD13,CD14,CD33,MPOe1a2/b2a2 [1]3 M 30 N/A 46,XY,t(9;22)(q34;q11.2)[20] CD10,CD19,CD22 CD7 CD13,MPO b3a2 [7]4 F 68 M2 47,XX,t(9;22)(q34,q11.2), þ 21[20]CD10,CD19,CD79a None CD13,CD33,MPO b2a2 Present study  Abbreviations:  no., number; FAB, French American British; F, female; M, male; N/A, not available.130  Letter to the editor / Cancer Genetics and Cytogenetics 188 (2009) 129 e 131  leukaemia: an entity with poor prognosis which is related to unfav-ourable cytogenetics and P-glycoprotein over-expression. Br J Hae-matol 1998;100:147 e 55.[2] Matutes E, Morilla R, Farahat N, Carbonell F, Swansbury J, Dyer M,Catovsky D. Definition of acute biphenotypic leukemia. Haematolog-ica 1997;82:64 e 6.[3] Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E,Orfao A, van’t Veer MB. Proposals for the immunological classi-fication of acute leukemias. European Group for the Immunologi-cal Characterization of Leukemias (EGIL). Leukemia 1995;9:1783 e 6.[4] Owaidah TM, Al Beihany A, Iqbal MA, Elkum N, Roberts GT. Cy-togenetics, molecular and ultrastructural characteristics of bipheno-typic acute leukemia identified by the EGIL scoring system.Leukemia 2006;20:620 e 6.[5] Sulak LE, Clare CN, Morale BA, Hansen KL, Montiel MM.Biphenotypic acute leukemia in adults. Am J Clin Pathol 1990;94:54 e 8.[6] Killick S, Matutes E, Powles RL, Hamblin M, Swansbury J,Treleaven JG, Zomas A, Atra A, Catovsky D. Outcome of bipheno-typic acute leukemia. Haematologica 1999;84:699 e 706.[7] Choi HW, Shin MG, Kim HJ, Lee IK, Yun JH, Kim HR, Kim YK,Yun HK, Cho D, Kee SJ, Shin JH, Suh SP, Ryang DW. Biphenotypicacute leukemiawith BCR-ABL mRNA transcript b3a2 type: a case re-port with review of the literature. Korean J Lab Med 2006;26:249 e 54.[8] Maru Y. Molecular biology of chronic myeloid leukemia. Int J Hem-atol 2001;73:308 e 22.[9] Jaffe ES, Harris NL, Stein H, Vardiman JW. Pathology and genetics:tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press,2001.[10] IzraeliS,RainisL,HertzbergL,SmoohaG,BirgerY.Trisomyofchro-mosome 21 in leukemogenesis. Blood Cells Mol Dis 2007;39:156 e 9.[11] Oka S, Yokote T, Akioka T, Hara S, Kobayashi K, Hirata Y,Hiraoka N, Tsuji M, Hanafusa T. Trisomy 21 as the sole acquiredkaryotypic abnormality in biphenotypic acute leukemia. IntJ Hematol 2007;85:270 e 2.131  Letter to the editor / Cancer Genetics and Cytogenetics 188 (2009) 129 e 131
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