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TET2 deficiency increases the competitive advantage of hematopoietic stem and progenitor cells through upregulation of thrombopoietin receptor signaling

Author

Listed:
  • Yitong Yang

    (University of Toronto
    University Health Network)

  • Severine Cathelin

    (University Health Network)

  • Alex C. H. Liu

    (University of Toronto
    University Health Network)

  • Amit Subedi

    (University Health Network)

  • Abdula Maher

    (University Health Network
    University of Toronto)

  • Mohsen Hosseini

    (University Health Network)

  • Dhanoop Manikoth Ayyathan

    (University Health Network)

  • Robert Vanner

    (University Health Network)

  • Steven M. Chan

    (University of Toronto
    University Health Network)

Abstract

Ten-Eleven Translocation-2 (TET2) mutations drive the expansion of mutant hematopoietic stem cells (HSCs) in clonal hematopoiesis (CH). However, the precise mechanisms by which TET2 mutations confer a competitive advantage to HSCs remain unclear. Here, through an epigenetic drug screen, we discover that inhibition of disruptor of telomeric silencing 1-like (DOT1L), a H3K79 methyltransferase, selectively reduces the fitness of Tet2 knockout (Tet2KO) hematopoietic stem and progenitor cells (HSPCs). Mechanistically, we find that TET2 deficiency increases H3K79 dimethylation and expression of Mpl, which encodes the thrombopoietin receptor (TPO-R). Correspondingly, TET2 deficiency is associated with a higher proportion of primitive Mpl-expressing (Mpl+) cells in the HSC compartment. Importantly, inhibition of Mpl expression or the signaling downstream of TPO-R is sufficient to reduce the competitive advantage of murine and human TET2-deficient HSPCs. Our findings demonstrate a critical role for aberrant TPO-R signaling in TET2 mutation-driven CH and uncover potential therapeutic strategies against this condition.

Suggested Citation

  • Yitong Yang & Severine Cathelin & Alex C. H. Liu & Amit Subedi & Abdula Maher & Mohsen Hosseini & Dhanoop Manikoth Ayyathan & Robert Vanner & Steven M. Chan, 2025. "TET2 deficiency increases the competitive advantage of hematopoietic stem and progenitor cells through upregulation of thrombopoietin receptor signaling," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57614-y
    DOI: 10.1038/s41467-025-57614-y
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    1. Giulia Schiroli & Vinay Kartha & Fabiana M. Duarte & Trine A. Kristiansen & Christina Mayerhofer & Rojesh Shrestha & Andrew Earl & Yan Hu & Tristan Tay & Catherine Rhee & Jason D. Buenrostro & David T, 2024. "Cell of origin epigenetic priming determines susceptibility to Tet2 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Wenyu Yu & Emma J. Chory & Amy K. Wernimont & Wolfram Tempel & Alex Scopton & Alexander Federation & Jason J. Marineau & Jun Qi & Dalia Barsyte-Lovejoy & Joanna Yi & Richard Marcellus & Roxana E. Iaco, 2012. "Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    3. Sagi Abelson & Grace Collord & Stanley W. K. Ng & Omer Weissbrod & Netta Mendelson Cohen & Elisabeth Niemeyer & Noam Barda & Philip C. Zuzarte & Lawrence Heisler & Yogi Sundaravadanam & Robert Luben &, 2018. "Prediction of acute myeloid leukaemia risk in healthy individuals," Nature, Nature, vol. 559(7714), pages 400-404, July.
    4. Shinsuke Ito & Ana C. D’Alessio & Olena V. Taranova & Kwonho Hong & Lawrence C. Sowers & Yi Zhang, 2010. "Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification," Nature, Nature, vol. 466(7310), pages 1129-1133, August.
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