Cell of origin epigenetic priming determines susceptibility to Tet2 mutation.
David T ScaddenVinay KarthaFabiana M DuarteTrine A KristiansenChristina MayerhoferRojesh ShresthaAndrew Scott EarlYan HuTristan TayCatherine RheeJason D BuenrostroDavid T ScaddenPublished in: Nature communications (2024)
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.
Keyphrases
- induced apoptosis
- dna methylation
- single cell
- gene expression
- cell therapy
- hematopoietic stem cell
- cell cycle arrest
- stem cells
- endoplasmic reticulum stress
- type diabetes
- acute myeloid leukemia
- bone marrow
- genome wide
- signaling pathway
- skeletal muscle
- oxidative stress
- cell death
- mesenchymal stem cells
- pseudomonas aeruginosa
- biofilm formation
- insulin resistance
- staphylococcus aureus
- copy number
- single molecule