美国波士顿儿童医院L. I. Zon研究组组取得一项新突破。他们表明抗炎症是增强克隆造血功能的基础。相关论文于2021年11月5日发表在《科学》杂志上。

他们开发了一种技术，将马赛克诱变与造血干细胞和祖细胞 (HSPC)的颜色标记相结合，以研究获得性突变如何影响局部环境中的克隆适应性。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 的双等位基因丢失废除了 asxl1 突变克隆建立克隆优势的能力。

这些结果支持了一个模型，其中突变体克隆的克隆适应性是由增强的对来自其突变体成熟细胞后代的炎症信号的抵抗力驱动的。

据了解，克隆造血是由突变的HSPC的适应性增强引起的，但此类克隆如何扩展尚不清楚。

附：英文原文

Title: Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis

Author: S. Avagyan, J. E. Henninger, W. P. Mannherz, M. Mistry, J. Yoon, S. Yang, M. C. Weber, J. L. Moore, L. I. Zon

Issue&Volume: 2021-11-05

Abstract: 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.

DOI: aba9304

Source: https://www.science.org/doi/10.1126/science.aba9304