BCR-ABL Truncation due to Premature Translation Termination as a Mechanism of Resistance to Kinase Inhibitors

Abstract

The Philadelphia (Ph) chromosome, a shortened version of chromosome 22, results from a reciprocal translocation between chromosomes 9q34 and 22q11 [1,2,3]. The Ph translocation positions the c-ABL gene of chromosome 9 downstream from the breakpoint cluster region (BCR) on chromosome 22; the resulting fusion gene produces a 190- or 210-kDa hybrid protein with constitutive kinase activity associated with chronic myelogenous leukemia (CML). The impressive clinical efficacy of imatinib mesylate, a selective and effective ABL kinase inhibitor, has revolutionized the treatment of CML. However, the development of resistance to imatinib, which occurs over months to years, constitutes a major drawback in the treatment of advanced CML [4, 5]. Mechanisms leading to drug resistance include amplification of the BCR-ABL gene, acquired additional genomic alterations, and most importantly, specific mutations within the ABL kinase domain that impede drug binding [2, 3,6,7,8].