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

Chang-Lung Lee, Katherine D. Castle, Everett J. Moding, Jordan M. Blum, Nerissa Williams, Lixia Luo, Yan Ma, Luke B. Borst, Yongbaek Kim and David G. Kirsch ()
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Chang-Lung Lee: Duke University Medical Center
Katherine D. Castle: Duke University Medical Center
Everett J. Moding: Duke University Medical Center
Jordan M. Blum: Duke University Medical Center
Nerissa Williams: Duke University Medical Center
Lixia Luo: Duke University Medical Center
Yan Ma: Duke University Medical Center
Luke B. Borst: College of Veterinary Medicine, North Carolina State University
Yongbaek Kim: Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University
David G. Kirsch: Duke University Medical Center

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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 KrasLA1 mice, we show that TBI promotes the expansion of a rare population of thymocytes that express oncogenic KrasG12D. However, blocking p53 during TBI significantly suppresses the expansion of KrasG12D-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.

Date: 2015
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DOI: 10.1038/ncomms9477

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