Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis

Jodi R. Alt, Timothy C. Greiner, John L. Cleveland, Christine M. Eischen

Research output: Contribution to journalArticle

99 Scopus citations

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 Eμ-myc transgenic mice. Mdm2+/-Eμ-myc transgenics had greatly protracted rates of B cell lymphoma development with life spans twice that of wild-type transgenic littermates. Impaired lymphoma development was associated with drastic reductions in peripheral B cell numbers in Mdm2+/-Eμ-myc transgenics, and primary pre-B cells from Mdm2+/-Eμ-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+/-Eμ-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.

Original languageEnglish (US)
Pages (from-to)1442-1450
Number of pages9
JournalEMBO Journal
Volume22
Issue number6
DOIs
StatePublished - Mar 17 2003

Keywords

  • Apoptosis
  • Lymphoma
  • Mdm2
  • Myc
  • P53

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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