Interference with differentiation is a major step in tumor progression. In myeloid cells deregulated expression of c-Myc blocks terminal differentiation, promoting both proliferation and an apoptotic response associated with the block in differentiation. The Myc mutants mycS and T58A each block myeloid differentiation without the apoptotic response, possibly being more aggressive oncogenes than wild type c-myc in myeloid cells. Eliminating Gadd45 expression influences the response of myeloid cells to deregulated Myc by eliminating the apoptotic response associated with the Myc-mediated block in differentiation;therefore Gadd45 genes behave as tumor suppressors. Acceleration of tumorigenesis in transgenic mouse models is observed when apoptosis is suppressed. Thus, it is hypothesized that the response of myeloid cells to deregulated Myc expression depends not only on the genetic status of Myc, but also on the status of the other genes expressed in the cell, including the Gadd45 family of genes. It is further hypothesized that the initial response of myeloid cells to c-Myc will have ramifications not only on how the cells respond to differentiation signals, but also long term effects with regard to proliferation and eventually leukemic transformation. Accordingly, three specific aims are proposed.
Aim I : Dissect the c-Myc Block in Terminal Differentiation and Its Associated Apoptosis Using c-Myc Mutant Proteins.
Aim II : Analyze the Effect of Deregulated Expression of c-Myc in Myeloid Cells Deficient in Gadd45.
Aim III : Identify and Assess the Role of Different c-Myc Target Genes, Including Gadd45b and Gadd45g, in Blocking Myeloid Differentiation and Activating Premature Apoptosis. These studies will lead to a greater understanding of how c-Myc participates in the neoplastic process by influencing proliferation rates. It will encompass how mutations in either c-Myc itself or in cellular genes, specifically the Gadd45 gene family, suppresses the Myc-mediated apoptotic response associated with the block in myeloid differentiation, enhancing the leukemic potential of c-Myc. This knowledge should provide novel tools for designing drugs to promote differentiation and/or apoptosis of leukemic cells.
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