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- Title
Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.
- Authors
Chen, Sisi; Wang, Qiang; Yu, Hao; Capitano, Maegan L.; Vemula, Sasidhar; Nabinger, Sarah C.; Gao, Rui; Yao, Chonghua; Kobayashi, Michihiro; Geng, Zhuangzhuang; Fahey, Aidan; Henley, Danielle; Liu, Stephen Z.; Barajas, Sergio; Cai, Wenjie; Wolf, Eric R.; Ramdas, Baskar; Cai, Zhigang; Gao, Hongyu; Luo, Na
- 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. Ageing is associated with clonal hematopoiesis of indeterminate potential (CHIP), which is linked to increased risks of hematological malignancies. Here the authors uncover an epigenetic mechanism through which mutant p53 drives clonal hematopoiesis through interaction with EZH2.
- Subjects
MUTANT proteins; REGULATION of hematopoiesis; EPIGENETICS; HEMATOPOIETIC stem cells; PROGENITOR cells
- Publication
Nature Communications, 2019, Vol 10, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-13542-2