Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 12 2019
11 12 2019
Historique:
received:
19
03
2019
accepted:
11
11
2019
entrez:
13
12
2019
pubmed:
13
12
2019
medline:
12
3
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31827082
doi: 10.1038/s41467-019-13542-2
pii: 10.1038/s41467-019-13542-2
pmc: PMC6906427
doi:
Substances chimiques
Histones
0
Tumor Suppressor Protein p53
0
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Ezh2 protein, mouse
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5649Subventions
Organisme : NCI NIH HHS
ID : F32 CA203049
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA134777
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM133496
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL150624
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA197369
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001108
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK105014
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK106846
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA101937
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL140961
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK119524
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL146137
Pays : United States
Commentaires et corrections
Type : ErratumIn
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