Our overall objective is to devise more selective treatment of CML. We previously reported 12 pTyr proteins constitutively tyrosine phosphorylated in CML but not in normal progenitors. All of these proteins have now been identified, including 3 novel proteins p62dok-1, p56dok-2, and SHIP2. The protein-protein and protein-phospholipid interactions involved in recognizing and initiating specific signals induced by specific cytokines or other molecules are extraordinarily complex, as are the molecular interactions involved in regulating the transmission of these signals and governing the appropriate cellular responses. Despite their complexity, we're making good progress in defining the interactions of several of the proteins involved in the pathogenesis of CML. In Project 1, Drs. Clarkson and Resh and coworkers are studying the roles of the Dok, SHIP and other proteins in the pathogenesis of CML, and in collaboration with Drs. Bornmann and Kuriyan, they are examining new compounds for their ability to selectively inhibit Abl kinase and other molecular targets. One compound (PD 173955) has recently been identified that is approximately 100-fold more inhibitory to Bcr-Abl than ST1571 and studies are underway to characterize this compound and to design and synthesize even more selective inhibitors. In Project 2, """"""""Dok proteins in ontogenesis and leukemogenesis"""""""" is the new title of Project #2. Dr. Pandolfi and coworkers have inactivated Dok-1, 2, & 3 genes in mice and are currently examining phenotypic changes in these mice as well as in intercrossed double and triple knockout mice with the goals of defining the roles of these proteins in ontogenesis, hematopoiesis, and leukemogenesis and to identify the genes critical for their function and for the pathogenesis of CML. In Project 3, Dr. Van Aelst and coworkers are studying the functional role of p62dok in p210bcr-abl and PDGFR signaling. Together with Dr. Pandolfi, they found that p62dok functions as a negative regulator of PDGF-induced cell proliferation and p210bcr-abl-mediated transformation, acting at least in part by negatively influencing the Ras/MAPK signaling pathway. They are currently studying the mechanism of inhibition and are characterizing the protein complexes associated with p62dok and p210bcr-abl. Together with Dr. Clarkson's group they will seek to identify and characterize the genes and signaling pathways affected by p210bcr-abl by microarray analysis both in cell lines and primary and CML progenitors. With Dr. M. Myers they will also map tyrosine phosphorylation sites in p62dok triggered by p210bcr-abl and PDGF, and try to identify additional p62dok-interacting proteins applying techniques of mass analysis and protein sequencing.
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