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Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

ABSTRACT:

Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to Tet2 mutation. Cell differentiation stage also influenced 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 sensitized 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.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic, Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

SUBMITTER: Giulia Schiroli

PROVIDER: MTBLS9914 | MetaboLights | 1970-01-01

REPOSITORIES: MetaboLights

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Dataset's files

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			Action	DRS
	MTBLS9914	Other
	FILES	Other
	a_MTBLS9914_LC-MS_alternating_hilic_metabolite_profiling.txt	Txt
	a_MTBLS9914_LC-MS_negative_hilic_metabolite_profiling-1.txt	Txt
	a_MTBLS9914_LC-MS_positive_hilic_metabolite_profiling-1.txt	Txt

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Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

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