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

Abstract

Genotoxic cancer therapies, such as chemoradiation, cause hematologic toxicity primarily by activating the tumor suppressor p53. While inhibiting p53-mediated cell death during cancer therapy ameliorates hematologic 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.

NF1+/− Hematopoietic Cells Accelerate Malignant Peripheral Nerve Sheath Tumor Development without Altering Chemotherapy Response

“…Whole bone marrow cells (WBMs) were isolated according to methods described previously (28). WBMs from donor mice with the indicated genotype and expressing tdTomato fluorescent protein were transplanted into 8-week-old recipient mice 6 hours after two fractions of 4.75 Gy total-body irradiation (TBI) with an interval of 18 hrs.…”

“…The dose rate was measured with an ion chamber by members of the Radiation Safety Division at Duke University. At 12 weeks after bone marrow transplantation, donor-derived engraftment of bone marrow cells in the peripheral blood was assessed by flow cytometry according to methods previously described (28). …”

Cancer Incidence in C3H Mice Protected from Lethal Total-Body Radiation after Amifostine

“…Aminothiols such as Amifostine are known to induce hypoxia when administered to animals (1, 22), thus, the protective effect of Amifostine on hematopoietic neoplasms could have resulted in part from bone marrow hypoxia. Recently reported studies suggest that lymphoma formation after TBI may be suppressed by hematopoietic stem/progenitor cells (HPSC), which originate from the bone marrow and can populate the thymus (9). After TBI, the HPSC cells are reduced in both the thymus and bone marrow and thus, B- and T-cells in the thymus, which are initiated to become tumorigenic, are potentially the source of radiation-induced lymphomas observed in our study, as well as other studies (9).…”

“…Recently reported studies suggest that lymphoma formation after TBI may be suppressed by hematopoietic stem/progenitor cells (HPSC), which originate from the bone marrow and can populate the thymus (9). After TBI, the HPSC cells are reduced in both the thymus and bone marrow and thus, B- and T-cells in the thymus, which are initiated to become tumorigenic, are potentially the source of radiation-induced lymphomas observed in our study, as well as other studies (9). The ability of Amifostine to protect the bone marrow and the HPSC cells (by whatever mechanism) may allow for the movement of the lymphoma-suppressing HPSC cells into the thymus, thus preventing or reducing lymphoma formation.…”

Reducing radiation-induced gastrointestinal toxicity — the role of the PHD/HIF axis

“…Importantly, inhibition of p53 with the small molecule pifithrin-α was proposed to limit radiation-induced apoptosis in normal tissues without compromising the radiosensitivity of the tumor xenografts. Targeting p53 with inhibitors such as pifithrin-α is not predicted to increase the chances of developing future tumors since altering the p53-mediated acute response to DNA damage does not appear to alter its tumor suppressor functions (50)(51)(52)(53). At a mechanistic level, p53 inhibition by pifithrin-α appeared to reduce p53-induced DNA replication arrest in tissues with high proliferation rates following whole-body irradiation.…”