C-, N-, AND L-MYC EFFECTS ON HEMATOPOIETIC CELLS

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Myc oncoproteins are involved in proliferation, differentiation, cell cycle progression, and apoptosis. The three major myc proteins, c-myc, N-myc, and L-myc, are also implicated in the pathogenesis of malignancies such as Burkitt's and AIDS-related lymphomas, breast cancer, neuroblastoma, and lung cancer. Little is known regarding the functional similarities of these proteins. We have shown that c-, N-, and L-myc differ in their ability to modulate c-myc-responsive promoters. Overexpression of c-myc is associated with increased sensitivity of hematopoietic cells to chemotherapeutic drugs whereas N-myc and L-myc produce resistance. In cells lacking p53, c-myc overexpression also produces genomic instability. In Specific Aim I, we will compare the abilities of c-, N-, and L-myc to restore normal levels of proliferation and transformation by c-myc-dependent oncogenes in c-myc-/- fibroblasts. In Specific Aim II, chimeric and mutant myc proteins will be used to map the domains responsible for imparting pharmacologic sensitivity or resistance to hematopoietic cells. In Specific Aim III, we will determine the role of cysteine proteases ("Caspases") in apoptosis mediated by c-, N-, and L-myc. Finally, in Specific Aim IV, we will again use mutant myc proteins to map the regions responsible for imparting genomic instability to hematopoietic cells lacking p53. We will ask if the overexpression of individual c-myc-regulated genes, is sufficient to produce genomic instability. Abnormalities of cyclins and their kinases will be examined. We will also ask if genes other than c-myc, which can induce unscheduled S-phase can substitute for c-myc in the induction of tetraploidy. Two different models for the induction of tetraploidy will also be tested. The above studies should provide new insights into how myc oncoproteins differ from one another with respect to the phenotypes they impart to hematopoietic cells.