Irradiation selects for p53-deficient hematopoietic progenitors.
Open accessAbstract
Identification and characterization of mutations that drive cancer evolution constitute a major focus of cancer research. Consequently, dominant paradigms attribute the tumorigenic effects of carcinogens in general and ionizing radiation in particular to their direct mutagenic action on genetic loci encoding oncogenes and tumor suppressor genes. However, the effects of irradiation are not limited to genetic loci that encode oncogenes and tumor suppressors, as irradiation induces a multitude of other changes both in the cells and their microenvironment which could potentially affect the selective effects of some oncogenic mutations. P53 is a key tumor suppressor, the loss of which can provide resistance to multiple genotoxic stimuli, including irradiation. Given that p53 null animals develop T-cell lymphomas with high penetrance and that irradiation dramatically accelerates lymphoma development in p53 heterozygous mice, we hypothesized that increased selection for p53-deficient cells contributes to the causal link between irradiation and induction of lymphoid malignancies. We sought to determine whether ionizing irradiation selects for p53-deficient hematopoietic progenitors in vivo using mouse models. We found that p53 disruption does not provide a clear selective advantage within an unstressed hematopoietic system or in previously irradiated BM allowed to recover from irradiation. In contrast, upon irradiation p53 disruption confers a dramatic selective advantage, leading to long-term expansion of p53-deficient clones and to increased lymphoma development. Selection for cells with disrupted p53 appears to be attributable to several factors: protection from acute irradiation-induced ablation of progenitor cells, prevention of irradiation-induced loss of clonogenic capacity for stem and progenitor cells, improved long-term maintenance of progenitor cell fitness, and the disabling/elimination of competing p53 wild-type progenitors. These studies indicate that the carcinogenic effect of ionizing irradiation can in part be explained by increased selection for cells with p53 disruption, which protects progenitor cells both from immediate elimination and from long-term reductions in fitness following irradiation.
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Residual BM injury can predispose irradiated individuals to develop leukemia and lymphoma by reducing the fitness of HSCs.
“In addition, residual BM injury can predispose irradiated individuals to develop leukemia and lymphoma by reducing the fitness of HSCs.7”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [7]
A prior study showed that Tp53+/− HSCs also have a competitive advantage following irradiation, which appeared to be due, at least in part, to reduced irradiation-induced senescence in Tp53+/− HSCs.
“Importantly, a prior study similarly showed that Tp53+/− HSCs also have a competitive advantage following irradiation, which appeared to be due, at least in part, to reduced irradiation-induced senescence in Tp53+/− HSCs 20,21.”
From Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia (2015) · cites this paper as [21]
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- Authors
- Marusyk, A., Porter, C. C., Zaberezhnyy, V., & DeGregori, J.
- Affiliations
- University of Colorado Anschutz (US)
- Corresponding author
- DeGregori, James
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-03-02
- Volume
- 8
- Issue
- 3
- Pages
- e1000324
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC2830447
- OpenAlex
- W2000738792
- Cited by
- 151
- References
- 51
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 6 · 2019: 8 · 2018: 4 · 2017: 11 · 2016: 18 · 2015: 9 · 2014: 11 · 2013: 11 · 2012: 6
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Cancer Institute (2 P30 CA46934, R01CA109657, T32CA082086, K12CA086913, P30CA046934)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- p53, ionizing radiation, hematopoietic progenitor cells, clonal selection, radiation-induced lymphoma, T-cell lymphoma, tumor suppressor, clonogenicity, radioresistance (biology), bone marrow, carcinogenesis
- MeSH terms
- Animals, Cells, Cultured, DNA Damage, Hematopoietic Stem Cells, Lymphoma, Mice, Inbred BALB C, Mutation, Radiation, Ionizing, Recombinant Fusion Proteins, Biomarkers, Bone Marrow Transplantation, Genes, p53, Tumor Suppressor Protein p53, Mice, Knockout, Hematopoietic Stem Cell Transplantation, Mice
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