The ABL1 protooncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Alterations of ABL1 by chromosomal rearrangement or viral transduction lead to ... The ABL1 protooncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Alterations of ABL1 by chromosomal rearrangement or viral transduction lead to malignant transformation, as in chronic myeloid leukemia (CML; 608232) (summary by Barila and Superti-Furga, 1998).
Clinical studies with the Abl tyrosine kinase inhibitor STI571 in CML demonstrated that many patients with advanced-stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical ... - Resistance to Tyrosine Kinase Inhibitors Clinical studies with the Abl tyrosine kinase inhibitor STI571 in CML demonstrated that many patients with advanced-stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, Gorre et al. (2001) found that the drug resistance was associated with a reactivation of BCR-ABL signal transduction in all cases examined. In 6 of 9 patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug (T315I; 189980.0001). This substitution was sufficient to confer STI571 resistance in a reconstitution experiment. In 3 patients, resistance was associated with progressive BCR-ABL gene amplification. Gorre et al. (2001) concluded that their studies provided evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggest a strategy for identifying inhibitors of STI571 resistance. Von Bubnoff et al. (2002) identified 5 distinct point mutations in the BCR-ABL kinase domain (see, e.g., 189980.0002-189980.0004) in 7 of 8 patients resistant to STI571 who were Ph-positive and had either CML or ALL. In this prospective study, analysis was done before treatment with STI571 and at time of relapse. Roche-Lestienne et al. (2002) showed that in some cases of STI571 resistance, ABL mutations (see, e.g., 189980.0005; 189980.0006) had originated prior to drug therapy, probably as secondary mutational events during the course of CML. Drug therapy may have resulted in clonal selection. Azam et al. (2003) stated that sequencing of the BCR-ABL gene in patients who relapsed after STI571 chemotherapy revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that confer STI571 resistance, they performed an in vitro screen of randomly mutagenized BCR-ABL and recovered all the major mutations previously identified in patients and numerous others that illuminated novel mechanisms of acquired drug resistance. Structural modeling implied that a novel class of variants acts allosterically to destabilize the autoinhibited conformation of the ABL kinase, to which STI571 preferentially binds. The authors concluded that this screening strategy is a paradigm applicable to a growing list of target-directed anticancer agents and provides a means of anticipating the drug-resistant amino acid substitutions that are likely to be clinically problematic. Goldman and Melo (2003) tabulated 19 mutations that had been found in association with imatinib resistance in patients with CML and Philadelphia chromosome-positive acute lymphoblastic leukemia. They also gave the proposed mechanism of resistance in the case of each mutation (see, e.g., 189980.0004-189980.0005). - Transformation of CML to ALL The Philadelphia chromosome is the defining lesion of chronic myelogenous leukemia and a subset of acute lymphoblastic leukemia. To define oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, Mullighan et al. (2008) performed a genomewide analysis of diagnostic leukemia samples from 304 individuals with ALL, including 43 BCR-ABL1 B-progenitor ALLs and 23 CML cases. IKZF1, encoding the transcription factor Ikaros (603023), was deleted in 83.7% of BCR-ABL1 ALL, but not in chronic phase CML. Deletion of IKZF1 was also identified as an acquired lesion at the time of transformation of CML to ALL (lymphoid blast crisis). The IKZF1 deletions resulted in haploinsufficiency, expression of a dominant-negative Ikaros isoform, or the complete loss of Ikaros expression. Sequencing of IKZF1 deletion breakpoints suggested that aberrant RAG-mediated recombination (see 179615) is responsible for the deletions. Mullighan et al. (2008) concluded that genetic lesions resulting in the loss of Ikaros function are an important event in the development of BCR-ABL1 ALL.