Cell of origin epigenetic priming determines susceptibility to Tet2 oncogenic mutation [bulk ATAC-seq]

Hematopoietic stem cell mutations can result in clonal hematopoiesis (CHIP) but the clinical outcomes are heterogeneous. The nature of the founder mutation and secondary mutations likely drive emergent neoplastic disease. We investigated how the cell state 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. Overall design: Hematopoietic clones conditionally immortalized from primary myeloid progenitors using HoxB8 retrovirus fused to Estrogen Receptor domain (Hoxb8-ER) were profiled by bulk ATAC-seq. 28 individual clones were generated from a Tet2 fl/fl mouse and each of them was divided into cohorts for induction of Tet2 KO or control. Each clone pair is derived from an individual GMP cell. 24 clone pairs were generated in the presence of SCF, which primes them towards granulocytic fate, and 4 of them were derived in the presence of GM-CSF which arrests them at a more mature stage and directs them towards a monocyte-macrophage fate.