Understanding of the basic cell biology that can lead to cancer is vital to our quest to eliminate the causes of these potentially fatal diseases and find new avenues for treatment. Over 95% of Chronic Myelogenous Lymphoma and 15% of Acute Lymphocytic Leukemia can be traced back to a chromosomal translocation that fuses the cellular Abl (c-Abl) gene with the Breakage Cluster region, resulting in the Bcr-Abl protein. This fusion protein leads to cancer in B cells, but exactly how this happens is not fully understood. We have found that c-Abl is active in pro-B cells, a population of B cells vital to immunity and antibody generation, but that can give rise to lymphoma when proliferation goes unchecked. Therefore, we believe that understanding the function of c-Abl in pro-B cells will provide considerable insight into the role of Abl proteins in cancer.
The specific aims of this proposal are 1) to test the hypothesis that c-Abl kinase functions in small pro-B cells; 2) to identify critical c-Abl functional domains; and 3) to identify phosphorylation substrates for c-Abl. We propose to analyze the function of c-Abl in pro-B cells by examining the subcellular localization of c-Abl in the B lineage and testing the role of c-Abl in the IL-7 signaling pathway. Additionally, we will identify which portions of c-Abl are critical for its function and identify proteins that are phosphorylated by c-Abl, a protein modification that can have significant affects on the function and stability of targets. Using bone marrow cultures and transplants, flow cytometry, and protein biochemistry we will address the function of c-Abl in the B cell lineage, with particular emphasis place on the pro-B cell stage. To understand the causes of cancer, we must understand the cellular processes that can lead to this disastrous outcome. The misregulation of key proteins can lead to unchecked cell proliferation, and may ultimately result in cancer. It is our goal to understand the normal function of the c-Abl protein, which when mutated can lead to cancer. Elucidating the normal role of this protein may shed light on the mechanisms by which its misregulation can lead to cancer. ? ? ?
