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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


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
Issue number1
StatePublished - Dec 1 2019
Externally publishedYes

ASJC Scopus subject areas

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


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