Chronic myeloid leukemias are caused by activated tyrosine kinase oncogenes, most often by BCR/ABL, or the related oncogenes TEL/ABL, TEL/JAK2, or TEL/PDGFR. The goal of this project is to understand in detail the signal transduction pathways activated by BCR/ABL and related oncogenes that are relevant for transformation of hematopoietic cells. Using BCR/ABL as the best-studied example, this kinase is believed to function by phosphorylating itself and adjacent cell proteins, and by phosphorylating other proteins that are brought in by adapter molecules. This results in activation of a variety of signaling pathways that ultimately block apoptosis, deregulate cell cycle control, alter adhesion and homing, and cause genetic instability. A particular focus of this project period will be phosphotidylinositol signaling, which we and others have shown is required for transformation, probably because of prominent effects on apoptosis and cell cycle deregulation. We would like to understand how PI3K is activated and determine the downstream targets particularly those related to viability signaling. Also, in preliminary studies we have shown that SHIP, an inositol 5-phophatase, is downregulated by BCR/ABL. SHIP activity would be expected to modulate the lipids that accumulated downstream of PI3K. This is of interest since a SHIP knock out mouse develops a myeloproliferative syndrome, suggesting that there may be certain PI3K products that are more important for hematopoiesis than others. Finally, efforts will be focused on understanding the differences in signaling by the 3 known forms of BCR/ABL, encoding p190, p210, or p230; and understanding the differences between BCR/ABL and v-ABL. In particular, pathways initiated because of phosphorylation of Y177 of BCR seem to be of particular interest, as this single tyrosine residue is needed to generate a myeloproliferative disorder in mice. Overall, identification of critical signaling intermediates will be useful for many reasons, but particularly to identify potential targets for drug development, especially for drugs that would be synergistic with STI571.
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