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Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

Author

Listed:
  • Sisi Chen

    (Indiana University
    Indiana University)

  • Qiang Wang

    (Pennsylvania State University)

  • Hao Yu

    (Indiana University)

  • Maegan L. Capitano

    (Indiana University)

  • Sasidhar Vemula

    (Indiana University)

  • Sarah C. Nabinger

    (Indiana University)

  • Rui Gao

    (Indiana University)

  • Chonghua Yao

    (Indiana University
    Shanghai University of Traditional Chinese Medicine)

  • Michihiro Kobayashi

    (Indiana University)

  • Zhuangzhuang Geng

    (Pennsylvania State University)

  • Aidan Fahey

    (Indiana University)

  • Danielle Henley

    (Indiana University)

  • Stephen Z. Liu

    (Indiana University)

  • Sergio Barajas

    (Indiana University)

  • Wenjie Cai

    (Indiana University)

  • Eric R. Wolf

    (Indiana University)

  • Baskar Ramdas

    (Indiana University)

  • Zhigang Cai

    (Indiana University)

  • Hongyu Gao

    (Indiana University)

  • Na Luo

    (Indiana University)

  • Yang Sun

    (Indiana University)

  • Terrence N. Wong

    (Washington University)

  • Daniel C. Link

    (Washington University)

  • Yunlong Liu

    (Indiana University)

  • H. Scott Boswell

    (Indiana University)

  • Lindsey D. Mayo

    (Indiana University)

  • Gang Huang

    (Cincinnati Children’s Hospital Medical Center)

  • Reuben Kapur

    (Indiana University)

  • Mervin C. Yoder

    (Indiana University)

  • Hal E. Broxmeyer

    (Indiana University)

  • Zhonghua Gao

    (Pennsylvania State University)

  • Yan Liu

    (Indiana University
    Indiana University)

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.

Suggested Citation

  • 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 , 2019. "Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13542-2
    DOI: 10.1038/s41467-019-13542-2
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    Cited by:

    1. Oriol Pich & Iker Reyes-Salazar & Abel Gonzalez-Perez & Nuria Lopez-Bigas, 2022. "Discovering the drivers of clonal hematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Kitty Sherwood & Joseph C. Ward & Ignacio Soriano & Lynn Martin & Archie Campbell & Raheleh Rahbari & Ioannis Kafetzopoulos & Duncan Sproul & Andrew Green & Julian R. Sampson & Alan Donaldson & Kai-Re, 2023. "Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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