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research
Our laboratory studies transformation and leukemogenesis by tyrosine kinases, with a particular focus on the ABL family. Bcr-Abl is the product of the t(9;22) Philadelphia chromosome translocation and is found in patients with chronic myeloid leukemia (CML) as well as acute B-lymphoblastic leukemia. A central tool in our approach to understanding the molecular pathogenesis of these leukemias is the ability to express the Bcr-Abl gene in the bone marrow of laboratory mice, a model system we developed over a decade ago that is now widely used in the study of leukemia and other blood cell disorders. Mice that receive a transplant of bone marrow transduced with a retrovirus expressing Bcr-Abl develop a fatal myeloproliferative syndrome that closely resembles human CML (see figure 1). We are currently using this system to analyze the critical signaling pathways necessary for development of leukemia and to test molecularly targeted drugs directed against these pathways.
A second major effort in the laboratory concerns the function and mechanism of regulation of the normal c-Abl tyrosine kinase. We are focusing on the regulation of c-Abl catalytic activity because Abl is the target of a small molecule inhibitor, imatinib mesylate, that was recently approved for the treatment of CML patients. Resistance to imatinib is frequently observed in patients with advanced CML and can be due to mutations in the Abl catalytic domain. We have developed methods to purify Abl kinases and characterize their enzymological properties. Using this assay, we demonstrated that Abl catalytic activity is regulated in a complex manner through the SH3 domain, by intracellular inhibitors, and via tyrosine phosphorylation (see figure 2). Other recent studies from our laboratory demonstrate that Bcr-Abl is regulated in much the same fashion. These studies illuminate the mechanisms of Abl kinase regulation and resistance to small molecule inhibitors, and provide information essential to the design of the next generation of Abl inhibitors.
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