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Philadelphia Chromosome Unmasked As a Secondary Genetic Change in Acute Myeloid Leukemia on Imatinib Treatment

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Philadelphia Chromosome Unmasked As a Secondary Genetic Change in Acute Myeloid Leukemia on Imatinib Treatment Letters to the Editor 2050 The ELL/MLLT1 dual-color assay described herein entails 3Department of Cytogenetics, City of Hope National Medical Center, Duarte, CA, USA and co-hybridization of probes for the ELL and MLLT1 gene regions, 4 each labeled in a different fluorochrome to allow differentiation Cytogenetics Laboratory, Seattle Cancer Care Alliance, between genes involved in 11q;19p chromosome translocations Seattle, WA, USA E-mail: [email protected] in interphase or metaphase cells. In t(11;19) acute leukemia cases, gain of a signal easily pinpoints the specific translocation breakpoint to either 19p13.1 or 19p13.3 and 11q23. In the References re-evaluation of our own cases in light of the FISH data, the 19p breakpoints were re-assigned in two patients, underscoring a 1 Harrison CJ, Mazzullo H, Cheung KL, Gerrard G, Jalali GR, Mehta A certain degree of difficulty in determining the precise 19p et al. Cytogenetic of multiple myeloma: interpretation of fluorescence in situ hybridization results. Br J Haematol 2003; 120: 944–952. breakpoint in acute leukemia specimens in the context of a 2 Thirman MJ, Levitan DA, Kobayashi H, Simon MC, Rowley JD. clinical cytogenetics laboratory. Furthermore, we speculate that Cloning of ELL, a gene that fuses to MLL in a t(11;19)(q23;p13.1) the ELL/MLLT1 probe set should detect other 19p translocations in acute myeloid leukemia. Proc Natl Acad Sci 1994; 91: 12110– that involve these genes with partners other than MLL. Accurate 12114. molecular classification of leukemia is becoming more im- 3 Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog of portant as targeted therapies are developed and diseases are Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 1992; 71: 691–700. further sub-classified based on the presence of particular genetic 4 Rubnitz JE, Behm FG, Curcio-Brint AM, Pinheiro VRP, Carroll AJ, mutations. Distinction of the correct breakpoint, and the gene Raimondi SC et al. Molecular analysis of t(11;19) breakpoints in involved on 19p, is a worthy goal for diagnosis of patients with childhood acute leukemias. Blood 1996; 87: 4804–4808. these cytogenetic aberrations. 5 Huret JL, Brizard A, Slater R, Charrin C, Bertheas MF, Guilhot F et al. Cytogenetic hetergeneity in t(11;19) acute leukemia: clinical, hematological and cytogenetic analysis of 48 patients – updated Acknowledgements published cases and 16 new observations. Leukemia 1993; 7: 152. 6 Moorman AV, Hagemeijer A, Charrin C, Rieder H, Secker-Walker LM. The translocations, t(11;19)(q23;p13.1) and t(11;19)(q23;p13.3): a cyto- This work was partially funded by a private donation from Pearl genetic and clinical profile of 53 patients. Leukemia 1998; 12: 805–810. Ruttenberg and family to MLS. 7 Cox MC, Panetta P, Lo-Coco F, Del Poeta G, Venditti A, Maurillo L 1 1 3 3 4 et al. Chromosomal aberration of the 11q23 locus in acute leukemia JS Biggerstaff , W Liu , ML Slovak , D Bobadilla , E Bryant , and frequency of MLL gene translocation. Am J Clin Pathol 2004; C Glotzbach2 and LG Shaffer2 1 122: 298–306. Cytogenetics Division, Sacred Heart Medical Center, 8 Shih LY, Lian DC, Fu JF, Wu JH, Wang PN, Lin TL et al. Spokane, WA, USA; Characterization of fusion partner genes in 114 patients with 2 Health Research and Education Center, Washington State de novo acute myeloid leukemia and MLL rearrangement. Leukemia University, Spokane, WA, USA; 2006; 20: 218–223. Philadelphia chromosome unmasked as a secondary genetic change in acute myeloid leukemia on imatinib treatment Leukemia (2006) 20, 2050–2051. doi:10.1038/sj.leu.2404407; 137 Â 109/l. Peripheral blood showed 65% blasts, 14% neu- published online 5 October 2006 trophils and 7% myeloid precursors. There was no basophilia. Marrow aspirate confirmed AML with 74% blasts and chromo- some analysis showed 45,XX,inv(3)(q21q26),À7,t(9;22)(q34; The Philadelphia chromosome (Ph), the cytogenetic hallmark of q11.2) [12]. Reverse transcriptase-polymerase chain reaction chronic myelogenous leukemia (CML) encodes p210BCR-ABL (RT-PCR) for BCR-ABL showed only the e1a2 transcripts. fusion protein with enhanced tyrosine kinase activity. In vitro Fluorescence in situ hybridization (FISH) analysis of 300 and animal model studies confirm the primary pathogenic marrow cells using dual fusion translocation probes (D-FISH, role of p210BCR-ABL fusion protein in the initiation and main- Vysis, Downers Grove, IL, USA)1 showed 83% were positive tenance of CML, and this has led to the successful develop- for BCR-ABL. The patient failed two cycles of AML induc- ment of kinase inhibitors such as imatinib in the control of tion chemotherapy using daunorubicin and cytarabine with the disease. In contrast, Ph chromosome-positive acute persistent leukemia and 78% of marrow cells positive for leukemia poses a biologic and clinical challenge given the BCR-ABL by FISH. Imatinib 600 mg daily was then started, difficulty in distinguishing de novo acute leukemia from bone marrow examination 6 weeks later still showed 15% blast-crisis presentation of CML, the role of p210BCR-ABL blasts. FISH studies showed no BCR-ABL-positive cells versus p190BCR-ABL protein kinases, and the variability of (sensitivity 0.3%); however, 39% marrow cells, including outcome and experience with use of imatinib. We describe segmented neutrophils, were positive for monosomy 7 using a patient who presented with Ph þ acute myeloid leukemia the a-satellite sequences in the centromeric region of (AML) with two additional clonal markers, in which imati- chromosome 7 (CEP7,D7Z1, Vysis). Cytogenetics showed poor nib unmasked the Ph chromosome as a secondary genetic growth, but one metaphase showed 45,XX,inv(3)(q21q26),À7. change. Taken together, these studies provide evidence that the A 49-year-old lady was admitted for pallor, weight loss Ph þ translocation is secondarily acquired in an initial clone and poor appetite. There was no splenomegaly. Hemoglobin characterized by inv(3)(q21q26),À7, which was unmasked was 3.6 g/dl, platelet 295 000/ml and white blood cells after the imatinib treatment. After 5 months of imatinib Leukemia Letters to the Editor 2051 treatment, marrow blasts increased to 40%. FISH for BCR-ABL 2Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China and remained negative (also negative with the sorted CD34 þ / 3 CD38 þ and CD34 þ /CD38- population) whereas À7 was Department of Pathology, Tuen Mun Hospital, present in 82% of the marrow cells. Quantitative PCR analysis Hong Kong SAR, China E-mail: [email protected] was not performed. However, with nested RT-PCR using sets of BIOMED primers2 the e1a2 transcript was still detectable suggesting presence of a very small and quiescent population References of imatinib-resistant BCR-ABL-positive leukemic stem cells. There are only a few reports on the use of imatinib in Ph þ 1 Yip SF, Wan TSK, Lie AKW, Liu HSY, Chan LC. Monitoring AML.3–7 Most cases reporting molecular remission with imatinib of chronic myeloid leukemia (CML) imatinib response by had short follow-up and long-term clinical and molecular data is fluorescence-in-situ hybridization (FISH). Blood 2005; 106 (Part not available. Our case of AML with 45,XX,inv(3)(q21q26),À7, 2): 289b. 2 van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, t(9;22)(q34;q11.2) shows two recognized secondary cytogenetic Saglio G et al. Standardized RT-PCR analysis of fusion gene anomalies in advanced CML, that is, monosomy 7 and chromo- transcripts from chromosome aberrations in acute leukemia for some aberrations involving band 3q21or 3q26,8 which initially detection of minimal residual disease. Report of the BIOMED-1 would have suggested a case of CML blast crisis. However, concerted action: investigation of minimal residual disease in acute simultaneous presence of À7 and inv(3)(q21q26) in blastic leukemia. Leukemia 1999; 13: 1901–1928. CML is rare (http://cgap.nci.nih.gov/Chromosomes). We propose 3 Cividin M, Brizard F, Sorel N, Renaud M, Guilhot F, Brizard A. p190(BCR-ABL) rearrangement as a secondary change in a case of that owing to the secondary nature of the Ph chromosome, acute myelo-monocytic leukemia with inv(16)(p13q22). Leuk Res the rarity in which these three cytogenetic changes are 2004; 28: 97–99. found together in blast crisis, the lack of p210BCR-ABL protein 4 Jentsch-Ullrich K, Pelz AF, Braun H, Koenigsmann M, Mohren M, transcript and the absence of splenomegaly, our case is more in Wieacker P et al. A Complete molecular remission in a patient with keeping with de novo Ph þ AML over myeloid blastic CML. Philadelphia-chromosome positive acute myeloid leukemia after conventional therapy and imatinib. Haematologica 2004; 89: This is confirmed by FISH studies, which revealed the Ph ECR15. chromosome is acquired as a late event during clonal evolution. 5 Viniou NA, Vassilakopoulos TP, Giakoumi X, Mantzouranis M, It is salutary to note that combination of FISH and RT-PCR Pangalis GA. Ida-FLAG plus imatinib mesylate-induced molecular analysis was needed to avoid the erroneous conclusion of remission in a patient with chemoresistant Ph1+ acute myeloid imatinib resistance as the size of the BCR-ABL clone went leukemia. Eur J Haematol 2004; 72: 58–60. down which is not compatible with BCR-ABL-dependent 6 Ito K, Tominaga K, Suzuki T, Jinnai I, Bessho M. Successful treat- imatinib resistance. ment with imatinib mesylate in a case of minor BCR-ABL-positive acute myelogenous leukemia. Int J Hematol 2005; 81: 242–245. 7 Yamaguchi M, Konishi I. Successful treatment with imatinib 1 1 2 3 1 mesylate for Philadelphia chromosome-positive refractory acute SF Yip , TSK Wan , HSY Liu , MLG Wong , C-C So myeloid leukemia.
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