Abstract

Mdm2 harnesses the p53 tumor suppressor, yet loss of one Mdm2 allele in Mdm2^+/- mice has heretofore not been shown to impair tumor development. Here we report that Mdm2 haplo-insufficiency profoundly suppresses lymphomagenesis in E-myc transgenic mice. Mdm2^+/-E-myc transgenics had greatly protracted rates of B cell lymphoma development with life spans twice that of wild-type transgenic littermates. Im paired lymphoma development was associated with drastic reductions in peripheral B cell numbers in Mdm2^+/-E-myc transgenics, and primary pre-B cells from Mdm2^+/-E-myc transgenics and Mdm2^+/- littermates were extremely susceptible to spontaneous apoptosis. Loss of p53 rescued all of the effects of Mdm2 haplo-insufficiency, indicating they were p53 dependent. Furthermore, half of the lymphomas that ultimately emerged in Mdm2^+/-E-myc transgenics harbored inactivating mutations in p53, and the majority overcame haplo-insufficiency by overexpressing Mdm2. These results support the concept that Mdm2 functions are rate limiting in lymphomagenesis and that targeting Mdm2 will enhance p53-mediated apoptosis, compromising tumor development and/or maintenance.