Irradiation Selects for p53-Deficient Hematopoietic Progenitors

Abstract

Author SummaryCancer progression can be understood through the framework of Darwinian evolution, which involves two major factors: genetic mutation and selection. Random mutations are thought to result in the initiation and phenotypic diversification of tumors, and environmental influences mediate selection for those mutations that increase tumor cell fitness. Since oncogenic mutations are necessary for the development of spontaneous malignancies and since experimental introduction of these mutations often leads to transformation and cancers, the causation of cancers by carcinogens is traditionally attributed to their induction of new mutations that are oncogenic. We instead asked whether selection for oncogenic mutations is affected by ionizing irradiation, an archetypal mutagenic carcinogen, by examining the selective effects of inactivation of the critical tumor suppressor gene p53. While disruption of p53 is selectively neutral in populations of unstressed hematopoietic progenitors, it provides a strong selective advantage upon irradiation. This selection of p53-deficient clones is attributable to protection from irradiation-induced cell death and loss of cellular fitness. Importantly, the selective expansion of irradiated cells bearing p53 disruption is blocked in the presence of non-irradiated wild-type competitors, indicating that the disabling of competing wild-type cells by irradiation is critical for selection of p53-deficient cells. Our results argue that induction of cancers by irradiation involves selection for mutations that confer radioresistance, and suggest that greater focus on how carcinogenic contexts impact on selection is warranted in understanding, preventing and treating cancers.