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Nat Commun. 2019 Dec 11;10(1):5649. doi: 10.1038/s41467-019-13542-2.

Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.

Author information

1
Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, 46202, USA.
2
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, 46202, USA.
3
Department of Biochemistry and Molecular Biology, the Cancer Institute, College of Medicine, Pennsylvania State University, Hershey, PA, 17033, USA.
4
Department of Microbiology and Immunology, Indiana University, Indianapolis, IN, 46202, USA.
5
Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
6
Department of Medical Genetics, Indiana University, Indianapolis, IN, 46202, USA.
7
Department of Ophthalmology, Indiana University, Indianapolis, IN, 46202, USA.
8
Siteman Cancer Center, Washington University, St. Louis, MO, 63110, USA.
9
Department of Medicine, Indiana University, Indianapolis, IN, 46202, USA.
10
Division of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
11
Department of Biochemistry and Molecular Biology, the Cancer Institute, College of Medicine, Pennsylvania State University, Hershey, PA, 17033, USA. zgao1@pennstatehealth.psu.edu.
12
Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, 46202, USA. liu219@iu.edu.
13
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, 46202, USA. liu219@iu.edu.

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.

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