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Genotoxic stresses promote clonal expansion of hematopoietic stem cells expressing mutant p53

Leukemia volume 32, pages 850–854 (2018)Cite this article

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Clonal hematopoiesis increases with age, where a single mutant hematopoietic stem or progenitor cell (HSPC) contributes to a significant, measurable clonal proportion of mature blood lineages.1, 2, 3, 4, 5 Evolution of mutant clonal hematopoiesis with age predisposes the elderly to myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and other aging-associated diseases, suggesting that mutations identified in hematopoietic stem cells (HSCs) contribute to disease development.1, 2, 3, 4, 5 However, the mechanisms by which age-induced stem cell mutations cause clonal expansion of HSCs are largely unknown.

Recently, acquired somatic mutations in TP53 gene were identified in the blood of aged healthy individuals and the frequency of TP53 mutations increases with age.3, 4, 5 TP53 mutations rank top five among mutations identified in aged healthy individuals.3, 4, 5 The TP53 gene, which encodes the tumor-suppressor p53, is the most frequent target for mutation in human cancer, including hematological malignancies.6 TP53 mutations are present in 10% of MDS cases and 20–30% in secondary MDS arising after exposure to radiation or alkylating agents.1, 7 The frequency of TP53 mutations in AML is approximately 10%. However, in AML with complex karyotype, the frequency of TP53 mutations and/or deletions is almost 70%.8 Further, TP53 mutations are associated with poor prognosis and decreased survival in MDS and AML.7, 8, 9 However, the role of TP53 mutations in clonal hematopoiesis and the pathogenesis of hematological malignancies is largely unknown.

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Acknowledgements

This work was supported in part by a NIH/NIA R56 award R56AG052501, a Department of Defense (DoD) Grant W81XWH-13-1-0187, a Career Development Award from the St. Baldrick’s Foundation, an Elsa Pardee Foundation New Investigator Award, a Leukemia Research Foundation New Investigator Award, a Showalter Trust Fund New Investigator Award, an Alex Lemonade Stand Foundation grant, a Children’s Leukemia Research Association grant and an American Cancer Society Institutional Research Grant to YL. We thank the Flow Cytometry Core and In vivo Therapeutic Core Laboratories, which were sponsored, in part, by the NIDDK Cooperative Center of Excellence in Hematology (CCEH) grant U54 DK106846. This work was supported, in part, by a Project Development Team within the ICTSI NIH/NCRR Grant Number UL1TR001108. We also thank Dr. Yang Xu at USCD for providing the p53R248W mice to the study.

Author contributions

SC and YL designed the research. SC, RG, CY, MK and SZL performed the research. SC and YL analyzed the data and performed the statistical analysis. MCY, HB, RK, HSB and LDM provided reagents and/or input to the study. SC and YL wrote the manuscript. All authors read, commented on and approved the manuscript.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    S Chen, L D Mayo & Y Liu

  2. Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    R Gao, C Yao, M Kobayashi, S Z Liu, M C Yoder, R Kapur, L D Mayo & Y Liu

  3. Department of Rheumatism, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    C Yao

  4. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    H Broxmeyer

  5. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    H S Boswell

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  1. S Chen
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Correspondence to Y Liu.

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Chen, S., Gao, R., Yao, C. et al. Genotoxic stresses promote clonal expansion of hematopoietic stem cells expressing mutant p53. Leukemia 32, 850–854 (2018). https://doi.org/10.1038/leu.2017.325

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