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A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases

Leukemia volume 25, pages 557–560 (2011)Cite this article

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Blast crisis (BC) is the terminal phase of chronic myeloid leukemia (CML) and is characterized by a rapid expansion of myeloid or lymphoid differentiation-arrested blast cells leading to short median survival.1, 2 In approximately 70% of cases the blast lineage is myeloid, whereas in 20–30% of cases the blasts are lymphoid.3 It has been suggested that the progression of CML to BC-CML is a two-step process. The initial step for chronic phase is the occurrence of the Philadelphia chromosome and genetic instability caused by the BCR–ABL tyrosine kinase.4 The second step is the acquisition of additional chromosomal aberrations or mutations of transcription factors by failed DNA repair processes.5 However, at present, little is known about the molecular mechanisms underlying disease progression, but, most likely, activation of oncogenic factors and/or mutations leading to loss of function of tumor suppressor genes in hematopoietic stem cells are involved.2 Only limited changes occurring during clonal evolution of chronic phase to BC, both resulting in altered gene expression patterns or DNA copy number alterations, have been described. We hypothesized that specific molecular alterations that regulate gene transcription occurring in other myeloid and lymphatic malignancies may be acquired during the malignant disease progression from chronic phase to BC.

In this study, in total, 39 BC-CML cases (n=24 myeloid, n=10 lymphoid, n=5 not specified) were analyzed to elucidate the molecular mechanisms underlying disease progression. Between September 2005 and July 2009, cells were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation. With respect to the karyotype, 12/34 cases analyzed (38.2%) harbored a t(9;22) translocation chromosome without additional chromosomal aberrations at BC-CML stage (cytogenetic data not available in five cases), whereas the other 22 cases carried additional alterations such as +8, +Philadelphia, +19, i(17)(q10), −7 and inv(3)(q21q26) (Table 1).

Table 1 Chromosomal and molecular aberrations in 39 BC-CML cases
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Authors and Affiliations

  1. MLL Munich Leukemia Laboratory, Munich, Germany

    V Grossmann, A Kohlmann, M Zenger, S Schindela, C Eder, S Weissmann, S Schnittger, W Kern, T Haferlach & C Haferlach

  2. III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany

    M C Müller

  3. Abteilung Hämatologie und Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    A Hochhaus

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  1. V Grossmann
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Correspondence to V Grossmann.

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Competing interests

CH, S Schnittger, WK, and TH have equity ownership of MLL Munich Leukemia Laboratory. VG, AK, MZ, CE, S Schindela, and SW are employed by MLL Munich Leukemia Laboratory. MCM and AH declare no conflict of interest.

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Grossmann, V., Kohlmann, A., Zenger, M. et al. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases. Leukemia 25, 557–560 (2011). https://doi.org/10.1038/leu.2010.298

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