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Molecular Biology and Cytogenetics of Chronic Myeloid Leukemia

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Neoplastic Diseases of the Blood

Abstract

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the t(9;22)(q34;q11) balanced reciprocal translocation that causes the fusion of a portion of chromosome 9 to chromosome 22 (der22), thereby replacing a fragment of chromosome 22 which fuses to chromosome 9 (der9). The resultant minute chromosome der22, designated as the Philadelphia chromosome (Ph), is the hallmark of CML [1]. The molecular event resulting from this translocation is the hybrid BCR-ABL1 oncogene, which encodes the constitutively active BCR-ABL1 protein kinase [1]. The BCR-ABL1 protein can transform cells through phosphorylation of tyrosine residues on a variety of intermediary proteins that transmits signals from the cytoplasm to the nucleus. The ultimate proof that BCR-ABL1 kinase expression can induce CML was furnished by experiments in which murine bone marrow was transfected with a retrovirus encoding BCR-ABL1 and transplanted into irradiated syngeneic recipients. Transplanted recipients developed several hematologic malignancies, most frequently a myeloproliferative syndrome that resembles very closely the chronic phase of CML [2]. The demonstration that the BCR-ABL1 kinase activity played a crucial role in cellular transformation provided the rationale for developing molecules aimed at targeting such activity. Kinase-based assays demonstrated that imatinib, the first tyrosine kinase inhibitor (TKI) developed for the treatment of CML, inhibited potently ABL1 kinase [3, 4], and more importantly, this inhibitory activity translated into impressive clinical activity [5]. The remarkable clinical success of imatinib propelled the rational design and development of other TKIs (e.g. nilotinib, dasatinib, bosutinib) aided by structural biology and high throughput medicinal chemistry methods. In spite of their clinical activity, patients receiving TKI therapy frequently harbor measurable amounts of residual disease, some may eventually fail TKI therapy, and in those with accelerated (AP) or blastic phase (BP) CML, responses are rare and, when they occur, typically short-lived [6]. These shortcomings of TKI therapy have spurred research efforts aimed at understanding the behavior of CML stem cells, the molecular basis of transformation to AP and BP, and the mechanisms of resistance to TKIs.

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Authors and Affiliations

  1. Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Blvd, Faculty Center Tower, Unit 428, Houston, TX, 77030, USA

    Alfonso Quintás Cardama M.D., Hagop Kantarjian M.D. & Jorge Cortes M.D.

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  1. Alfonso Quintás Cardama M.D.
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  2. Hagop Kantarjian M.D.
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  3. Jorge Cortes M.D.
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  1. Beth Israel Hospital, Cancer Center, St. Lukes-Roosevelt Hospital Center, 10th Avenue 1000, New York, 10019, New York, USA

    Peter H. Wiernik

  2. , Department of Hematology, Imperial College of London, Du Cane Road 150, London, W12 0NN, United Kingdom

    John M. Goldman

  3. Continuum Cancer Centers, Department of Medicine, St. Luke's-Roosevelt Hospital Center, 10th Avenue 1000, New York, 10019, New York, USA

    Janice P. Dutcher

  4. , Division of Hematology, Mayo Clinic, First Street SW. 200, Rochester, 55905, Minnesota, USA

    Robert A. Kyle

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Cardama, A.Q., Kantarjian, H., Cortes, J. (2013). Molecular Biology and Cytogenetics of Chronic Myeloid Leukemia. In: Wiernik, P., Goldman, J., Dutcher, J., Kyle, R. (eds) Neoplastic Diseases of the Blood. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3764-2_4

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