Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

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 () and David T. Scadden ()
Additional contact information
Giulia Schiroli: Massachusetts General Hospital
Vinay Kartha: Harvard University
Fabiana M. Duarte: Harvard University
Trine A. Kristiansen: Massachusetts General Hospital
Christina Mayerhofer: Massachusetts General Hospital
Rojesh Shrestha: Harvard University
Andrew Earl: Harvard University
Yan Hu: Harvard University
Tristan Tay: Harvard University
Catherine Rhee: Massachusetts General Hospital
Jason D. Buenrostro: Harvard University
David T. Scadden: Massachusetts General Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigate how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we find that the epigenetic features of clones at similar differentiation status are highly heterogeneous and functionally respond differently to Tet2 mutation. Cell differentiation stage also influences Tet2 mutation response indicating that the cell of origin’s epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitizes cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.

Date: 2024
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DOI: 10.1038/s41467-024-48508-6

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