Dept. of Cell and Developmental Biology
Oregon Health & Science University
The Bcr-Abl tyrosine kinase causes CML and is the target for therapy by imatinib, a clinically successful kinase inhibitor. More than 80% of newly diagnosed patients with chronic-phase chronic myeloid leukemia achieve a complete cytogenetic response (CCR) with imatinib treatment. However, patients who relapse during imatinib therapy often harbor mutations in the kinase domain of BCR-ABL that are imatinib-resistant. In this dissertation, three scerarios of acquired BCR-ABL mutations during imatinib therapy were studied. First, the presence of kinase domain mutations in the setting of minimal residual disease was investigated in patients with a stable CCR. Mutations were detected in a subset of these patients and were those commonly associated with drug resistance. However, detection of BCR-ABL kinase domain mutations in patients with a stable CCR did not consistently predict relapse. Second, mutations outside the kinase domain in the regulatory linker, SH2, SH3 and Cap domains were investigated. Imatinib-resistant mutations in these domains have been described in vitro, but not yet in patients. Mutations in the regulatory domains of Bcr-Abl were found in patients during imatinib treatment, but only a single mutation proved to be substantially imatinib-resistant. Third, deletion mutants of Bcr-Abl are described to occur in a subset of CML patients, apparently the result of missplicing. Most commonly these deletion mutants lack a significant portion of the kinase domain that includes the P-loop. These mutants are demonstrated to be catalytically inactive. We hypothesized that coexpressed Bcr-Abl deletion mutants would have a dominant-negative effect on the native form through the oligomerization domain of Bcr. Although such an effect was not found on signaling activity or growth factor independence, cells coexpressing deletion mutants did have increased imatinib sensitivity compared to cells expressing only native Bcr-Abl. In summary, the Bcr-Abl oncogene is a frequent site for mutagenesis during imatinib treatment, and the consequences of the mutations are diverse.
School of Medicine
Sherbenou, Daniel Wayne, "BCR-ABL mutations in chronic myeloid leukemia patients" (2007). Scholar Archive. 830.