Abstract 4812: p53 acts during total-body irradiation to promote lymphomagenesis

Radiation therapy can cause acute toxicity and long-term side effects including radiation-induced cancer. Because some of the short-term side effects of radiation are due to p53-mediated apoptosis, blocking p53 during radiation can protect some normal tissues from acute radiation injury and might improve the therapeutic ratio of radiation therapy. However, temporarily blocking p53 could also increase late effects of radiation because mice in which p53 is permanently deleted are sensitized to radiation-induced carcinogenesis. Experiments using a mouse model where p53 can be temporarily turned on during irradiation suggest that radiation-induced apoptosis does not contribute to p53-mediated tumor suppression. Here, we perform reciprocal experiments and temporarily turn p53 off during total-body irradiation (TBI) using transgenic mice with reversible RNA interference (shp53). Our results show that temporary p53 knockdown during TBI suppressed death from bone marrow failure by protecting hematopoietic stem and progenitor cells (HSPCs) against radiation. Remarkably, we found that temporary knockdown of p53 during TBI not only ameliorated acute hematological toxicity, but also prevented lymphoma development. In contrast, p53 knockdown during and permanently after TBI sensitized mice to radiation-induced carcinogenesis, which recapitulates the tumor spectrum of p53+/− mice exposed to irradiation. Mechanistic studies show that, by blocking apoptosis in hematopoietic cells, p53 knockdown during TBI suppressed accelerated repopulation of HSPCs, a critical step that facilitates expansion of pre-malignant clones with mutations after irradiation. Taken together, our results demonstrate that, although p53 is indispensible to suppress tumor formation after radiation, p53 functions during TBI to promote lymphoma formation.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4812. doi:1538-7445.AM2012-4812

Duke Scholars

Author David Guy Kirsch Radiation Oncology