Chronic myelogenous leukemia (CML) is a malignancy of a pluripotent hematopoietic stem cell. The disease is characterized by the presence of a specific chromosomal translocation, t(9;22), which results in the production of a 210 kDa fusion protein termed Bcr-Abl. As compared to c-Abl, the fusion protein, Bcr-Abl, has elevated tyrosine kinase activity. Over the past 5 years, numerous substrates of the Bcr-Abl tyrosine kinase have been identified and a variety of signaling pathways have been shown to be activated in Bcr-Abl-expressing cells. However, the necessity of most of these pathways and tyrosine phosphorylated protein for Bcr-Abl function remain unclear. Given the complexity of Bcr-Abl, it is the applicant's belief that a combination of approaches is required to dissect Bcr-Abl function. This includes a mutagenic structure-function analysis, a biochemical analysis of protein-protein interactions, and a genetic approach. This proposal will continue the studies by Bcr-Abl function by: 1. Analyzing Bcr-Abl mutants for defects in transforming abilities in vitro and in vivo; 2. Performing biochemical analyses of Bcr-Abl kinase regulation by tyrosine phosphorylation and determining affinities of interactions with various signaling proteins, and 3. Determining the necessity of various signaling proteins for Bcr-Abl function by analyzing cell lines or mice deficient in specific proteins. Through these studies the applicant hopes to gain greater insight into the molecular mechanism of action of this activated tyrosine kinase and that this information may be applied to disorders in which activated tyrosine kinase signaling pathways have a role.
Showing the most recent 10 out of 23 publications
