THE ROLE OF SRC FAMILY TYROSINE KINASES IN BCR-ABL SIGNAL TRANSDUCTION AND CHRONIC MYELOGENOUS LEUKEMIA

摘要: The hallmark of chronic myelogenous leukemia (CML) is the Philadelphia chromosome, which arises from reciprocal translocation c-abl proto-onogene on chromosome 9 and bcr locus 22. This results in expression a 210 kDa fusion protein (Bcr-Abl) with constitutive tyrosine kinase activity that responsible for CML pathogenesis. Bcr-Abl activates several signaling proteins important proliferation survival myeloid progenitors, including Src family kinases Hck Lyn, Stat5 transcription factor upstream components Ras/Erk pathway. Previous work our laboratory found kinase-defective blocks Bcr-Abl-induced transformation DAGM cells to cytokine independence, suggesting activation may be essential oncogenic by Bcr-Abl. Chapter II explores contribution vivo, using selective inhibitors. Inhibition Ph+ cell lines resulted growth arrest, induction apoptosis blocked Erk activaton downstream. These data implicate downstream Bcr-Abl, identify myeloid-specific as potential drug targets CML. In III, I investigated biochemical interactions between members Hck, Lyn Fyn each bind domain, C-terminal tail, SH3/SH2 region strongly phosphorylated SH3-SH2 vitro. Seven residues were identified substitution these phenylalanine context full-length TF-1 independence. position tyrosines crystal structure c-Abl defect mutant suggest phosphorylation impact autoregulation signaling. Taken together, firmly establish an role Bcr-Abl-mediated promising therapeutic target leukemia.