Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
Science. 2021 Nov 5;374(6568):768-772. doi: 10.1126/science.aba9304. Epub 2021 Nov 4.
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 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, , abrogated the ability of 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.
克隆性造血是由于突变的造血干/祖细胞（HSPC）获得性优势而产生，但此类克隆如何扩增尚不清楚。我们开发了一种技术，该技术将嵌合体突变与 HSPC 的颜色标记相结合，用于研究获得性突变如何在天然环境中影响克隆适应性。与克隆性造血相关的基因（如 RUNX1 或 TET2）中的突变促进了克隆优势。单细胞转录组分析显示，突变刺激了成熟髓系细胞中促炎基因和突变克隆祖细胞中抗炎基因的表达。此类免疫调节剂之一的 （IDH1/IDH2）的双等位基因缺失，削弱了突变克隆建立克隆优势的能力。这些结果支持这样一种模型，即突变克隆的克隆适应性是由其突变成熟细胞后代的炎症信号增强抵抗能力所驱动的。
