Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

dc.contributor.authorChen, Sisi
dc.contributor.authorWang, Qiang
dc.contributor.authorYu, Hao
dc.contributor.authorCapitano, Maegan L.
dc.contributor.authorVemula, Sasidhar
dc.contributor.authorNabinger, Sarah C.
dc.contributor.authorGao, Rui
dc.contributor.authorYao, Chonghua
dc.contributor.authorKobayashi, Michihiro
dc.contributor.authorGeng, Zhuangzhuang
dc.contributor.authorFahey, Aidan
dc.contributor.authorHenley, Danielle
dc.contributor.authorLiu, Stephen Z.
dc.contributor.authorBarajas, Sergio
dc.contributor.authorSergio, Wenjie
dc.contributor.authorWolf, Eric R.
dc.contributor.authorRamdas, Baskar
dc.contributor.authorCai, Zhigang
dc.contributor.authorGao, Hongyu
dc.contributor.authorLuo, Na
dc.contributor.authorSun, Yang
dc.contributor.authorWong, Terrence N.
dc.contributor.authorLink, Daniel C.
dc.contributor.authorLiu, Yunlong
dc.contributor.authorBoswell, H. Scott
dc.contributor.authorMayo, Lindsey D.
dc.contributor.authorHuang, Gang
dc.contributor.authorKapur, Reuben
dc.contributor.authorYoder, Mervin C.
dc.contributor.authorBroxmeyer, Hal E.
dc.contributor.authorGao, Zhonghua
dc.contributor.authorLiu, Yan
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicineen_US
dc.date.accessioned2020-03-13T14:01:49Z
dc.date.available2020-03-13T14:01:49Z
dc.date.issued2019-12-11
dc.description.abstractClonal 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.en_US
dc.identifier.citationChen, S., Wang, Q., Yu, H., Capitano, M. L., Vemula, S., Nabinger, S. C., ... & Fahey, A. (2019). Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway. Nature communications, 10(1), 1-14. 10.1038/s41467-019-13542-2en_US
dc.identifier.issn2041-1723en_US
dc.identifier.urihttps://hdl.handle.net/1805/22309
dc.language.isoen_USen_US
dc.publisherNature Researchen_US
dc.relation.isversionof10.1038/s41467-019-13542-2en_US
dc.relation.journalNature Communicationsen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0*
dc.sourcePMCen_US
dc.subjectStem cellsen_US
dc.subjectHaematopoietic stem cellsen_US
dc.subjectClonal hematopoiesis of indeterminate potentialen_US
dc.subjectHematopoietic stem and progenitor cellen_US
dc.subjectmutant p53en_US
dc.titleMutant p53 drives clonal hematopoiesis through modulating epigenetic pathwayen_US
dc.typeArticleen_US
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