Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis.

Alt JR, Greiner TC, Cleveland JL, Eischen CM
EMBO J. 2003 22 (6): 1442-50

PMID: 12628936 · PMCID: PMC151074 · DOI:10.1093/emboj/cdg133

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 micro -myc transgenic mice. Mdm2(+/-)E micro -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 micro -myc transgenics, and primary pre-B cells from Mdm2(+/-)E micro -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 micro -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.

MeSH Terms (18)

Animals Apoptosis B-Lymphocytes Cells, Cultured Cell Survival Gene Expression Regulation, Neoplastic Genes, myc Genes, p53 Genes, Tumor Suppressor Longevity Lymphoma, B-Cell Mice Mice, Knockout Mice, Transgenic Neoplasm Proteins Nuclear Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-mdm2

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