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^*

^*Corresponding author for this work

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

60 Scopus citations

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
Externally published	Yes

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1038/s41467-019-13542-2

Cite this

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{c3986747a9c04da0a4768b4e933baa6c,

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 = "Funding Information: This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Bone Marrow Failure Research Program—Idea Development Award under Award No. W81XWH-18–1–0265 to Y.L. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. This work was also supported in part by R01HL150624, R56DK119524, R56AG05250, and a Leukemia & Lymphoma Society (LLS) Translational Research Program Grant 6581–20 to Y.L. S.C.N. was supported by a NIH F32 Award 1F32CA203049. The authors would like to acknowledge the Flow Cytometry Core and In vivo Therapeutic Core Laboratories, which were sponsored, in part, by the NIDDK Cooperative Center of Excellence in Hematology (CCEH) grant U54 DK106846. This work was supported, in part, by a Project Development Team within the ICTSI NIH/ NCRR Grant Number UL1TR001108. We would like to thank Dr. Yang Xu at USCD for providing the p53R248W mice and Dr. Daniel G Tenen at Harvard Medical School for providing the Cebpα plasmid to the study. 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",

publisher = "Nature Publishing Group",

number = "1",

}

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

N1 - Funding Information: This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Bone Marrow Failure Research Program—Idea Development Award under Award No. W81XWH-18–1–0265 to Y.L. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. This work was also supported in part by R01HL150624, R56DK119524, R56AG05250, and a Leukemia & Lymphoma Society (LLS) Translational Research Program Grant 6581–20 to Y.L. S.C.N. was supported by a NIH F32 Award 1F32CA203049. The authors would like to acknowledge the Flow Cytometry Core and In vivo Therapeutic Core Laboratories, which were sponsored, in part, by the NIDDK Cooperative Center of Excellence in Hematology (CCEH) grant U54 DK106846. This work was supported, in part, by a Project Development Team within the ICTSI NIH/ NCRR Grant Number UL1TR001108. We would like to thank Dr. Yang Xu at USCD for providing the p53R248W mice and Dr. Daniel G Tenen at Harvard Medical School for providing the Cebpα plasmid to the study. Publisher Copyright: © 2019, The Author(s).

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.

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

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this