Molecular pathogenesis of chronic myeloid leukemia: implications for new therapeutic strategies

Abstract

 With an annual incidence of about ten in 1,000,000 people, chronic myeloid leukemia (CML) accounts for most cases of myeloproliferative disease and for 20% of all leukemias. While novel therapies such as treatment with interferon-α or bone marrow transplantation have successively improved the outcome of CML treatment, hope for future progress in the therapy of CML lies in an almost unique feature of this hematological malignancy. In contrast to many other forms or subforms of leukemias which display a great diversity in chromosomal alterations, most cases (>95%) of CML seem to be caused by an almost invariably found cytogenetic aberration, the so-called Philadelphia chromosome (Ph), resulting in the bcr-abl fusion gene. Its gene product, p210^bcr-abl (Bcr-Abl), is believed to be essential for hematopoietic cell transformation and seems to exert its effects by interfering with cellular signal transduction pathways, normally involved in the control of cell death and proliferation. Several partially interacting pathways have been shown to be induced by Bcr-Abl. The role of most of them is still unclear and, as understanding their biological functions should lead to novel therapeutic strategies on a molecular basis, much effort is spent on identifying their precise roles in CML. This review focuses on our current understanding of Bcr-Abl-induced signal transduction and outlines its importance for the biological effects of Bcr-Abl.