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Acute DNA damage activates the tumour suppressor p53 to promote radiation-induced lymphoma
Acute DNA damage activates the tumour suppressor p53 to promote radiation-induced lymphoma NATURE COMMUNICATIONS Lee, C., Castle, K. D., Moding, E. J., Blum, J. M., Williams, N., Luo, L., Ma, Y., Borst, L. B., Kim, Y., Kirsch, D. G. 2015; 6: 8477Abstract
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.
View details for PubMedID 26399548