美国贝勒医学院Margaret A. Goodell研究团队发现，SRCAP突变通过表观遗传和DNA修复失调驱动克隆造血。相关论文于2023年10月19日在线发表于国际学术期刊《细胞—干细胞》。

研究人员描述了导致造血干细胞（HSC）中SRCAP基因突变富集的背景和机制。研究表明，SRCAP突变会在人类细胞和小鼠体内产生选择性优势，使其接受蒽环类化疗药物多柔比星治疗和骨髓移植。此外，Srcap突变会导致淋巴细胞偏向性扩张，其驱动力是SRCAP调控的H2A.Z富集的丧失和DNA修复的增加。

总之，研究人员证明了SRCAP在干细胞和祖细胞多种途径的交叉点上运行，为促进造血系统中干细胞竞争的遗传变异的功能影响提供了一个新的视角。

研究人员表示，随着年龄的增长，所有细胞中的体细胞突变都会累积，并可能带来选择性优势，导致克隆扩增。在造血细胞中，调控DNA修复或表观遗传学的部分基因突变经常导致克隆造血（CH）。

附：英文原文

Title: SRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulation

Author: Chun-Wei Chen, Linda Zhang, Ravi Dutta, Abhishek Niroula, Peter G. Miller, Christopher J. Gibson, Alexander G. Bick, Jaime M. Reyes, Yi-Tang Lee, Ayala Tovy, Tianpeng Gu, Sarah Waldvogel, Yi-Hung Chen, Bryan J. Venters, Pierre-Olivier Estève, Sriharsa Pradhan, Michael-Christopher Keogh, Pradeep Natarajan, Koichi Takahashi, Adam S. Sperling, Margaret A. Goodell

Issue&Volume: 2023-10-19

Abstract: Somatic mutations accumulate in all cells with age and can confer a selective advantage,leading to clonal expansion over time. In hematopoietic cells, mutations in a subsetof genes regulating DNA repair or epigenetics frequently lead to clonal hematopoiesis(CH). Here, we describe the context and mechanisms that lead to enrichment of hematopoieticstem cells (HSCs) with mutations in SRCAP, which encodes a chromatin remodeler that also influences DNA repair. We show thatSRCAP mutations confer a selective advantage in human cells and in mice upon treatmentwith the anthracycline-class chemotherapeutic doxorubicin and bone marrow transplantation.Furthermore, Srcap mutations lead to a lymphoid-biased expansion, driven by loss of SRCAP-regulatedH2A.Z deposition and increased DNA repair. Altogether, we demonstrate that SRCAP operatesat the intersection of multiple pathways in stem and progenitor cells, offering anew perspective on the functional impact of genetic variants that promote stem cellcompetition in the hematopoietic system.

DOI: 10.1016/j.stem.2023.09.011

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00358-2