title: Acute DNA damage activates the tumour suppressor p53 to promote radiation-induced lymphoma.
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 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.
authors.affiliation: 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.
authors.forename: Chang-Lung
authors.initials: CL
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Castle
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Everett J
authors.initials: EJ
authors.lastname: Moding
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Blum
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Nerissa
authors.initials: N
authors.lastname: Williams
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA.
authors.forename: Luke B
authors.initials: LB
authors.lastname: Borst
authors.affiliation: Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea.
authors.forename: Yongbaek
authors.initials: Y
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D004249:DNA Damage / Q000235:genetics*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D015151:Immunoblotting; D008223:Lymphoma / Q000209:etiology / Q000235:genetics*; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060168:Thymocytes / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014916:Whole-Body Irradiation / Q000009:adverse effects*
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)