Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.

当造血干细胞 （HSC） 获得突变时，就会出现克隆造血 （CH），最常见的是 DNMT3A 和 TET2 基因，通过尚不清楚的机制赋予竞争优势。为了深入了解 CH 突变如何实现逐渐克隆扩增，我们对人 CH 骨髓 （BM） 样本使用了具有高保真基因分型的单细胞多组学。突变细胞的大部分选择性优势发生在 HSC 中。DNMT3A 和 TET2 突变克隆在早期祖细胞中进一步扩增，而 TET2 突变以剂量依赖性方式加速骨髓成熟。出乎意料的是，与来自非 CH 样本的 HSC 相比，来自 CH 样本的突变和非突变 HSC 都富含炎症和衰老转录组特征，揭示了非细胞自主效应。然而，相对于同一样本中的野生型 HSC，DNMT3A 和 TET2 突变 HSC 的炎症反应减弱。我们的数据支持一个模型，即 CH 克隆是逐渐选择的，因为它们对炎症和衰老的有害影响具有抵抗力。