Cell of origin epigenetic priming determines susceptibility toTet2mutation

Abstract

AbstractHematopoietic stem cell mutations can result in clonal hematopoiesis (CH) but the clinical outcomes are heterogeneous. The nature of the founder mutation and secondary mutations likely drive emergent neoplastic disease. We investigated how the state of the cell of origin where theTet2mutation occurs affects susceptibility to that commonly occurring CH mutation. Here, we provide evidence that risk is written in the epigenome of the cell of origin. By characterizing cell states that underlie myeloid differentiation and linking this information to an inducible system to assess myeloid progenitor clones, we provide evidence that epigenetic markers of the cell whereTet2mutation occurs stratifies clonal behaviors. Specifically, Sox4 fosters a global cell state of high sensitization towardsTet2KO. Using GMP and primary HSC models, we show that Sox4 promotes cell dedifferentiation, alters cell metabolism and increases the in vivo clonal output of mutant cells. Our results validate the hypothesis that epigenetic features can predispose specific clones for dominance and explain why an identical mutation can result in different outcomes.