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.
Highlights
Genotoxic cancer therapies, such as chemoradiation, cause haematological toxicity primarily by activating the tumour suppressor p53
To explore the role of p53 in radiation carcinogenesis in a model system with intact p53, we use transgenic mice that harbour an inducible in vivo short hairpin RNA (shRNA) against p53 to ask a reciprocal question: what happens to tumour development when p53 is temporarily turned off during irradiation in p53 wild type (WT) mice? To our surprise, we find that knockdown of p53 during total-body irradiation (TBI) ameliorates acute haematologic toxicity, and improves long-term survival of mice by preventing the formation of thymic lymphoma
Temporary knockdown of p53 during TBI significantly protected Lineage À Sca[1] þ cKit þ (LSK) cells, which are enriched for haematopoietic stem/progenitor cells (HSPCs)[19], against radiation injury (Fig. 1e–g) and improved survival of mice from the haematopoietic acute radiation syndrome[20] (Fig. 1h,i)
Summary
Genotoxic cancer therapies, such as chemoradiation, cause haematological toxicity primarily by activating the tumour suppressor p53. We utilize a mouse model of inducible p53 short hairpin RNA (shRNA) to show that temporarily blocking p53 during total-body irradiation (TBI) ameliorates acute toxicity, and improves long-term survival by preventing lymphoma development. Prior work by Christophorou and colleagues examined the role of p53 in the development of thymic lymphoma after total-body irradiation (TBI) utilizing p53ER knock-in mice that were functionally p53 null in the absence of tamoxifen treatment[14] They showed that treatment with tamoxifen to restore p53 during TBI markedly induced apoptosis, but did not impact lymphoma formation after radiation exposure. These results demonstrate that the acute p53 response to radiation is dispensable for suppressing the development of lymphomas in mice that have permanently lost p53 In contrast to these elegant mouse models, most cancer patients do not harbour germline p53 mutations. To explore the role of p53 in radiation carcinogenesis in a model system with intact p53, we use transgenic mice that harbour an inducible in vivo shRNA against p53 (ref. 17) to ask a reciprocal question: what happens to tumour development when p53 is temporarily turned off during irradiation in p53 WT mice? To our surprise, we find that knockdown of p53 during TBI ameliorates acute haematologic toxicity, and improves long-term survival of mice by preventing the formation of thymic lymphoma
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