Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

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.

造血干细胞（Hematopoietic stem cell, HSC）突变可引发克隆性造血（clonal hematopoiesis, CH），其临床结局呈现异质性。本研究旨在探究Tet2突变发生前的细胞状态如何影响恶性前表型。我们采用可诱导系统开展髓系祖细胞的克隆分析，结果发现，处于相似分化状态的克隆其表观遗传特征具有高度异质性，且对Tet2突变的功能响应存在显著差异。细胞分化阶段同样会影响Tet2突变的响应效果，这表明起源细胞的表观基因组可调控克隆性造血过程中克隆的特异性行为。与高风险临床结局相关的分子特征包括Sox4基因：该基因可使细胞对Tet2失活敏感，诱导去分化、改变细胞代谢，并增强突变细胞的体内克隆扩增能力，这一结论在原代粒细胞-巨噬细胞祖细胞（Granulocyte-Macrophage Progenitor, GMP）和造血干细胞模型中得到了验证。本研究结果验证了"表观遗传特征可使特定克隆获得增殖优势"这一假说，解释了为何相同的基因突变可导致不同的表型。