Acute DNA damage activates the tumour suppressor p53 to promote radiation-induced lymphoma.

Journal Article (Journal Article)

Genotoxic cancer therapies, such as chemoradiation, cause haematological toxicity primarily by activating the tumour suppressor p53. While inhibiting p53-mediated cell death during cancer therapy ameliorates haematologic toxicity, whether it also impacts carcinogenesis remains unclear. Here we utilize a mouse model of inducible p53 short hairpin RNA (shRNA) to show that temporarily blocking p53 during total-body irradiation (TBI) not only ameliorates acute toxicity, but also improves long-term survival by preventing lymphoma development. Using Kras(LA1) mice, we show that TBI promotes the expansion of a rare population of thymocytes that express oncogenic Kras(G12D). However, blocking p53 during TBI significantly suppresses the expansion of Kras(G12D)-expressing thymocytes. Mechanistically, bone marrow transplant experiments demonstrate that TBI activates p53 to decrease the ability of bone marrow cells to suppress lymphoma development through a non-cell-autonomous mechanism. Together, our results demonstrate that the p53 response to acute DNA damage promotes the development of radiation-induced lymphoma.

Full Text

Duke Authors

Cited Authors

  • Lee, C-L; Castle, KD; Moding, EJ; Blum, JM; Williams, N; Luo, L; Ma, Y; Borst, LB; Kim, Y; Kirsch, DG

Published Date

  • September 24, 2015

Published In

Volume / Issue

  • 6 /

Start / End Page

  • 8477 -

PubMed ID

  • 26399548

Pubmed Central ID

  • PMC4586051

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms9477


  • eng

Conference Location

  • England