Loss of ATM or H2AX accelerates MYC-induced tumorigenesis and prevents sustained tumor regression Free

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The MYC oncogene has been commonly implicated in human tumorigenesis. Previously, the Felsher laboratory has developed a conditional transgenic model system employing the Tet system to regulate MYC expression in vivo in murine lymphocytes. Using this model system, we have shown that upon MYC inactivation, hematopoietic tumors undergo sustained regression associated with proliferative arrest, differentiation, and apoptosis of tumor cells. The mechanism by which MYC inactivation leads to tumor regression is not known. We speculated that that the DNA damage response may play a role in MYC induced tumorigenesis. We have found that MYC-induced lymphomas exhibit increased levels of activated DNA damage related proteins, such as ATM and H2AX. When combined with a genetic deficiency in ATM or H2AX, mice overexpressing MYC develop tumors more rapidly and following MYC inactivation, MYC ATM-/- or H2AX-/- tumors also fail to undergo sustained tumor regression. The DNA damage response appears to play an important role in delaying MYC-induced tumorigenesis and for maintaining tumor regression. We are currently investigating the mechanism by which deficiency of ATM or H2AX promotes tumorigenesis and prevents sustained regression upon MYC inactivation.