SRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulation.-猫眼课题宝

DOI：

10.1016/j.stem.2023.09.011

发表时间：

2023-10

期刊：

Cell stem cell

影响因子：

23.9

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Chun-Wei Chen;Linda Zhang;Ravi Dutta;A. Niroula;Peter G. Miller;Christopher J. Gibson;A. Bick;Jaime M. Reyes;Yi-Tang Lee;A. Tovy;Tianpeng Gu;Sarah M. Waldvogel;Yi-Hung Chen;Bryan J. Venters;P. Estève;S. Pradhan;M. Keogh;Pradeep Natarajan;Koichi Takahashi;A. Sperling;M. Goodell

随着年龄的增长，体细胞突变在所有细胞中积累，并且可以赋予选择性优势，导致随着时间的推移克隆扩增。在造血细胞中，调节DNA修复或表观遗传学的基因子集的突变经常导致克隆造血（CH）。在这里，我们描述的背景和机制，导致富集造血干细胞（HSC）与突变inSRCAP，它编码的染色质重塑，也影响DNA修复。我们发现SRCAP突变在人细胞和小鼠中给予蒽环类化疗药物阿霉素和骨髓移植治疗后具有选择性优势。此外，Srcapmutations导致淋巴细胞偏向性扩增，由SRCAP调节的H2A.Z沉积的丧失和DNA修复的增加驱动。总之，我们证明了SRCAP在干细胞和祖细胞中的多个途径的交叉点上起作用，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新的视角。

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 subset of genes regulating DNA repair or epigenetics frequently lead to clonal hematopoiesis (CH). Here, we describe the context and mechanisms that lead to enrichment of hematopoietic stem cells (HSCs) with mutations inSRCAP, which encodes a chromatin remodeler that also influences DNA repair. We show thatSRCAPmutations confer a selective advantage in human cells and in mice upon treatment with the anthracycline-class chemotherapeutic doxorubicin and bone marrow transplantation. Furthermore,Srcapmutations lead to a lymphoid-biased expansion, driven by loss of SRCAP-regulated H2A.Z deposition and increased DNA repair. Altogether, we demonstrate that SRCAP operates at the intersection of multiple pathways in stem and progenitor cells, offering a new perspective on the functional impact of genetic variants that promote stem cell competition in the hematopoietic system.

SRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulation.

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