Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

Hematopoietic 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 the Tet2 mutation 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 where Tet2 mutation occurs stratifies clonal behaviors. Specifically, Sox4 fosters a global cell state of high sensitization towards Tet2 KO. 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. ### Competing Interest Statement G.S. is currently an employee of Tessera Therapeutics. D.T.S. is a founder, director and stockholder of Magenta Therapeutics, Clear Creek Bio, and Lightning Biotherapeutics. He is a director of Agios Pharmaceuticals, Editas Medicine and Sonata Therapeutics and a founder and stockholder of Fate Therapeutics and Garuda Therapeutics. He is a consultant for VCanBio and SAB member of Simcere Pharmaceuticals and Garuda Therapeutics. J.D.B. holds patents related to ATAC-seq and is an SAB member of Camp4 and seqWell.