Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML. 1. Introduction Chronic myeloid leukemia (CML) is a myeloproliferative disorder that results from the reciprocal translocation of the ABL1 oncogene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22 [t(9; 22)], leading to the formation of the BCR-ABL oncoprotein. The shortened chromosome 22 formed by this translocation is the Philadelphia (Ph) chromosome. The BCR-ABL fusion oncogene, which is responsible for the pathogenesis of CML, has greatly enhanced ABL1 tyrosine kinase constitutive activity [1]. CML is characterized by a biphasic evolutive course. Most patients are diagnosed in the chronic phase (CML-CP), which is characterized by the absence of symptoms in half of the patients. However, a prominent leukocytosis is frequently observed by routine testing. In the other half of patients, symptoms are common and include splenomegaly, weight loss, lethargy, and anemia [2]. The disease may progress either directly to blast phase (BP) or through an intermediate accelerated phase (AP). The time course for progression to BP is variable and the molecular mechanisms underlying disease progression are extremely complex. BCR-ABL-dependent pathways to blast transformation include an increase in genomic instability, telomere shortening, loss of tumor-suppressor function, and inhibition of tumor suppressors with cell regulatory functions [2, 3]. In order to identify prognostic factors for CML patients, many clinical and biological characteristics have been analyzed. Sokal risk score
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