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 Luo; Yang 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

doi:10.1038/s41467-019-13542-2

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

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	5649
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13542-2
State	Published - Dec 1 2019

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Chen, S., Wang, Q., Yu, H., Capitano, M. L., Vemula, S., Nabinger, S. C., Gao, R., Yao, C., Kobayashi, M., Geng, Z., Fahey, A., Henley, D., Liu, S. Z., Barajas, S., Cai, W., Wolf, E. R., Ramdas, B., Cai, Z., Gao, H., ... Liu, Y. (2019). Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway. Nature communications, 10(1), Article 5649. https://doi.org/10.1038/s41467-019-13542-2

@article{c2910265d2604de4803cc6e305157c6b,

title = "Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway",

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.",

author = "Sisi Chen and Qiang Wang and Hao Yu and Capitano, {Maegan L.} and Sasidhar Vemula and Nabinger, {Sarah C.} and Rui Gao and Chonghua Yao and Michihiro Kobayashi and Zhuangzhuang Geng and Aidan Fahey and Danielle Henley and Liu, {Stephen Z.} and Sergio Barajas and Wenjie Cai and Wolf, {Eric R.} and Baskar Ramdas and Zhigang Cai and Hongyu Gao and Na Luo and Yang Sun and Wong, {Terrence N.} and Link, {Daniel C.} and Yunlong Liu and Boswell, {H. Scott} and Mayo, {Lindsey D.} and Gang Huang and Reuben Kapur and Yoder, {Mervin C.} and Broxmeyer, {Hal E.} and Zhonghua Gao and Yan Liu",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13542-2",

language = "English (US)",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

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Chen, S, Wang, Q, Yu, H, Capitano, ML, Vemula, S, Nabinger, SC, Gao, R, Yao, C, Kobayashi, M, Geng, Z, Fahey, A, Henley, D, Liu, SZ, Barajas, S, Cai, W, Wolf, ER, Ramdas, B, Cai, Z, Gao, H, Luo, N, Sun, Y, Wong, TN, Link, DC, Liu, Y, Boswell, HS, Mayo, LD, Huang, G, Kapur, R, Yoder, MC, Broxmeyer, HE, Gao, Z & Liu, Y 2019, 'Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway', Nature communications, vol. 10, no. 1, 5649. https://doi.org/10.1038/s41467-019-13542-2

TY - JOUR

T1 - Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

AU - Chen, Sisi

AU - Wang, Qiang

AU - Yu, Hao

AU - Capitano, Maegan L.

AU - Vemula, Sasidhar

AU - Nabinger, Sarah C.

AU - Gao, Rui

AU - Yao, Chonghua

AU - Kobayashi, Michihiro

AU - Geng, Zhuangzhuang

AU - Fahey, Aidan

AU - Henley, Danielle

AU - Liu, Stephen Z.

AU - Barajas, Sergio

AU - Cai, Wenjie

AU - Wolf, Eric R.

AU - Ramdas, Baskar

AU - Cai, Zhigang

AU - Gao, Hongyu

AU - Luo, Na

AU - Sun, Yang

AU - Wong, Terrence N.

AU - Link, Daniel C.

AU - Liu, Yunlong

AU - Boswell, H. Scott

AU - Mayo, Lindsey D.

AU - Huang, Gang

AU - Kapur, Reuben

AU - Yoder, Mervin C.

AU - Broxmeyer, Hal E.

AU - Gao, Zhonghua

AU - Liu, Yan

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85076373705&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-13542-2

DO - 10.1038/s41467-019-13542-2

M3 - Article

C2 - 31827082

AN - SCOPUS:85076373705

SN - 2041-1723

VL - 10

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5649

ER -

Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

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