Clonal hematopoiesis results from enhanced fitness of a mutant hematopoietic stem and progenitor cell (HSPC), but how such clones expand is unclear. We developed a technique that combines mosaic mutagenesis with color labeling of HSPCs to study how acquired mutations affect clonal fitness in a native environment. Mutations in clonal hematopoiesis–associated genes such as asxl1 promoted clonal dominance. Single-cell transcriptional analysis revealed that mutations stimulated expression of proinflammatory genes in mature myeloid cells and anti-inflammatory genes in progenitor cells of the mutant clone. Biallelic loss of one such immunomodulator, nr4a1, abrogated the ability of asxl1-mutant clones to establish clonal dominance. These results support a model where clonal fitness of mutant clones is driven by enhanced resistance to inflammatory signals from their mutant mature cell progeny.

中文翻译：

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对炎症的抵抗力是克隆造血增强适应性的基础

克隆造血是由突变的造血干细胞和祖细胞 (HSPC) 的适应性增强造成的，但这些克隆如何扩增尚不清楚。我们开发了一种将马赛克诱变与 HSPC 的颜色标记相结合的技术，以研究获得性突变如何影响原生环境中的克隆适应度。克隆造血相关基因如asxl1的突变促进了克隆优势。单细胞转录分析显示突变刺激了成熟骨髓细胞中促炎基因和突变克隆祖细胞中抗炎基因的表达。一种这样的免疫调节剂nr4a1的双等位基因丧失消除了asxl1-的能力突变克隆建立克隆优势。这些结果支持一个模型，其中突变克隆的克隆适应性是由对来自其突变成熟细胞后代的炎症信号的增强抗性驱动的。