Apoptosis resistance in chronic myelogenous leukemia

The chronic myeloid leukemia (CML) is the three-phase myeloproliferative disorder, dependent on the expression of the oncoprotein Bcr-Abl, which is the product of the reciprocal translocation between chromosomes 9 and 22, resulting in the Philadelphia chromosome (Ph). Bcr-Abl protein is the constitutively activated tyrosine kinase responsible for changes in intracellular biochemical cascades, culminating into hematopoieticic stem cell malignant transformation. CML leukemic cells present abnormal adhesion to medullar stroma, altered proliferation and an amazing resistance to apoptosis induced by classical chemotherapeutic drugs. Another therapy used in CML patients is imatinib mesylate (Gleeveca), which has shown remarkable clinical activity in these patients. However, this drug does not completely eradicate BCRABL-expressing cells from the body, and recently some patients showed resistance to imatinib. The observation that production of Bcr-Abl is the initiating event in CML drew attention to the survival signals triggered by this oncogene. The number of altered signal transducers and transcription factors has been associated with the anti-apoptotic phenotype of CML cells, and some of them lead to the expression and/or activation of apoptosis modulators from Bcl-2 family, such as Bcl-x L, Bcl-2, Bax and Bad. In this article we review some recent data on the understanding of Bcr-Abl oncoprotein expression effect in the apoptosis machinery in CML.