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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.

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


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.

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