Dmp1 is haplo-insufficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomas

Abstract

Loss of Dmp1, an Arf transcriptional activator, leads to spontaneous tumorigenesis in mice, causing death from various forms of cancer by two years of age. Retention and expression of the wild-typeDmp1 allele in tumors arising in Dmp1+/−mice demonstrate that Dmp1 can be haplo-insufficient for tumor suppression. The mean latency of Eμ-Myc-induced B-cell lymphomas is halved on a Dmp1−/− orDmp1+/− genetic background. Although p53mutations or Arf deletion normally occur in ∼50% of Eμ-Myc-induced lymphomas, Dmp1 loss obviates selection for such mutations, indicating that Dmp1 is a potent genetic modifier of the Arf–p53 pathway in vivo.