Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

Sisi Chen, Qiang Wang, Hao Yu, Maegan L. Capitano, Sasidhar Vemula, Sarah C. Nabinger, Rui Gao, Chonghua Yao, Michihiro Kobayashi, Zhuangzhuang Geng, Aidan Fahey, Danielle Henley, Stephen Z. Liu, Sergio Barajas, Wenjie Cai, Eric R. Wolf, Baskar Ramdas, Zhigang Cai, Hongyu Gao, Na LuoYang Sun, Terrence N. Wong, Daniel C. Link, Yunlong Liu, H. Scott Boswell, Lindsey D. Mayo, Gang Huang, Reuben Kapur, Mervin C. Yoder, Hal E. Broxmeyer, Zhonghua Gao, Yan Liu

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.

Original languageEnglish (US)
Article number5649
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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  • Cite this

    Chen, S., Wang, Q., Yu, H., Capitano, M. L., Vemula, S., Nabinger, S. C., Gao, R., Yao, C., Kobayashi, M., Geng, Z., Fahey, A., Henley, D., Liu, S. Z., Barajas, S., Cai, W., Wolf, E. R., Ramdas, B., Cai, Z., Gao, H., ... Liu, Y. (2019). Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway. Nature communications, 10(1), [5649]. https://doi.org/10.1038/s41467-019-13542-2