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Philadelphia chromosome unmasked as a secondary genetic change in acute myeloid leukemia on imatinib treatment

Leukemia volume 20, pages 2050–2051 (2006)Cite this article

The Philadelphia chromosome (Ph), the cytogenetic hallmark of chronic myelogenous leukemia (CML) encodes p210BCR-ABL fusion protein with enhanced tyrosine kinase activity. In vitro and animal model studies confirm the primary pathogenic role of p210BCR-ABL fusion protein in the initiation and maintenance of CML, and this has led to the successful development of kinase inhibitors such as imatinib in the control of the disease. In contrast, Ph chromosome-positive acute leukemia poses a biologic and clinical challenge given the difficulty in distinguishing de novo acute leukemia from blast-crisis presentation of CML, the role of p210BCR-ABL versus p190BCR-ABL protein kinases, and the variability of outcome and experience with use of imatinib. We describe a patient who presented with Ph+ acute myeloid leukemia (AML) with two additional clonal markers, in which imatinib unmasked the Ph chromosome as a secondary genetic change.

A 49-year-old lady was admitted for pallor, weight loss and poor appetite. There was no splenomegaly. Hemoglobin was 3.6 g/dl, platelet 295 000/μl and white blood cells 137 × 109/l. Peripheral blood showed 65% blasts, 14% neutrophils and 7% myeloid precursors. There was no basophilia. Marrow aspirate confirmed AML with 74% blasts and chromosome analysis showed 45,XX,inv(3)(q21q26),−7,t(9;22)(q34;q11.2) [12]. Reverse transcriptase-polymerase chain reaction (RT-PCR) for BCR-ABL showed only the e1a2 transcripts. Fluorescence in situ hybridization (FISH) analysis of 300 marrow cells using dual fusion translocation probes (D-FISH, Vysis, Downers Grove, IL, USA)1 showed 83% were positive for BCR-ABL. The patient failed two cycles of AML induction chemotherapy using daunorubicin and cytarabine with persistent leukemia and 78% of marrow cells positive for BCR-ABL by FISH. Imatinib 600 mg daily was then started, bone marrow examination 6 weeks later still showed 15% blasts. FISH studies showed no BCR-ABL-positive cells (sensitivity 0.3%); however, 39% marrow cells, including segmented neutrophils, were positive for monosomy 7 using the α-satellite sequences in the centromeric region of chromosome 7 (CEP7,D7Z1, Vysis). Cytogenetics showed poor growth, but one metaphase showed 45,XX,inv(3)(q21q26),−7. Taken together, these studies provide evidence that the Ph+ translocation is secondarily acquired in an initial clone characterized by inv(3)(q21q26),−7, which was unmasked after the imatinib treatment. After 5 months of imatinib treatment, marrow blasts increased to 40%. FISH for BCR-ABL remained negative (also negative with the sorted CD34+/CD38+ and CD34+/CD38- population) whereas −7 was present in 82% of the marrow cells. Quantitative PCR analysis 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 of imatinib-resistant BCR-ABL-positive leukemic stem cells.

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Authors and Affiliations

  1. Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China

    S F Yip, T S K Wan, C-C So & L C Chan

  2. Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China

    H S Y Liu

  3. Department of Pathology, Tuen Mun Hospital, Hong Kong SAR, China

    M L G Wong

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  1. S F Yip
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  2. T S K Wan
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Correspondence to S F Yip.

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Yip, S., Wan, T., Liu, H. et al. Philadelphia chromosome unmasked as a secondary genetic change in acute myeloid leukemia on imatinib treatment. Leukemia 20, 2050–2051 (2006). https://doi.org/10.1038/sj.leu.2404407

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