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Nat Commun. 2015 Sep 24;6:8477. doi: 10.1038/ncomms9477.

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

Author information

1
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
2
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
3
Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA.
4
Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea.

Abstract

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.

PMID:
26399548
PMCID:
PMC4586051
DOI:
10.1038/ncomms9477
[Indexed for MEDLINE]
Free PMC Article

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