title: Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis.
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 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.
authors.affiliation: Eppley Institute for Cancer Research, Department of Pathology and Microbiology, 987696 University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Jodi R
authors.initials: JR
authors.lastname: Alt
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Greiner
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eischen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology; D002470:Cell Survival; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D016259:Genes, myc; D016158:Genes, p53; D008136:Longevity; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2
chemical_list: D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2