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BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia

Oncogene volume 21, pages 8547–8559 (2002)Cite this article

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder resulting from the clonal expansion of a transformed multipotent hematopoietic stem cell. CML is a biphasic disease with an initial chronic phase characterized by a massive expansion of myeloid precursors and mature cells that leave the bone marrow (BM) prematurely but retain their capacity to differentiate normally. This is invariably followed by progression to a fatal acute phase termed ‘blast crisis’, which resembles acute leukemia (Spiers, 1977). Allogeneic stem cell transplantation (SCT) is the only curative treatment for CML patients, but it is available to a limited number of patients due to age of the patient and donor availability. Interferon-α constitutes a second therapeutic option for CML patients, and complete hematological and cytogenetic remission could be achieved in 10–20% of CML patients. At the molecular level, CML is characterized by the Philadelphia chromosome (Ph) resulting from a balanced translocation between chromosome 9 and 22 which leads to the formation of the BCR/ABL fusion gene (Nowell and Hungerford, 1960). Over the last two decades, a large number of studies has evaluated the molecular and cellular mechanisms contributing to CML, and a number of signaling pathways activated by BCR/ABL were elucidated. This progress in the understanding of the molecular pathophysiology of CML has led to the development of several novel therapeutic approaches targeting various steps of the malignant transformation. Some of these show promising results. This review will first describe the molecular pathophysiology of CML, then discuss novel therapeutic strategies developed for the treatment of CML targeting specific molecular events and preclinical and clinical studies.

The crucial genetic events in CML is the generation in a hematopoietic stem cell of a t(9;22)(q34;q11) reciprocal chromosomal translocation. This translocation between the long arms of chromosome 9 and 22 results in a shortened chromosome 22, commonly known as the Philadelphia chromosome (Ph) and found in over 90% of CML patients (Nowell and Hungerford, 1960). The molecular consequences of this translocation event is the formation of the chimeric gene BCR/ABL on chromosome 22 (Rowley, 1973) and a reciprocal ABL/BCR on chromosome 9. The later gene, although transcriptionally active, does not appear to have any functional role in CML and no ABL/BCR protein has, as yet, been identified (Diamond et al., 1995; Melo et al., 1993).

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  1. Cancer Center and Department of Medicine, Stem Cell Institute, University of Minnesota Cancer Center, Minneapolis, 55455, Minnesota, MN, USA

    Stephanie Salesse & Catherine M Verfaillie

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Salesse, S., Verfaillie, C. BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene 21, 8547–8559 (2002). https://doi.org/10.1038/sj.onc.1206082

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