Zhang Christine R, Ostrander Elizabeth L, Kukhar Ostap, Mallaney Cates, Sun Jiameng, Haussler Emily, Celik Hamza, Koh Won Kyun, King Katherine Y, Gontarz Paul, Challen Grant A
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Blood Cancer Discov. 2022 May 5;3(3):220-239. doi: 10.1158/2643-3230.BCD-21-0132.
Clonal hematopoiesis (CH) refers to the age-related expansion of specific clones in the blood system, and manifests from somatic mutations acquired in hematopoietic stem cells (HSCs). Most CH variants occur in the gene DNMT3A, but while DNMT3A-mutant CH becomes almost ubiquitous in aging humans, a unifying molecular mechanism to illuminate how DNMT3A-mutant HSCs outcompete their counterparts is lacking. Here, we used interferon gamma (IFNγ) as a model to study the mechanisms by which Dnmt3a mutations increase HSC fitness under hematopoietic stress. We found Dnmt3a-mutant HSCs resist IFNγ-mediated depletion, and IFNγ-signaling is required for clonal expansion of Dnmt3a-mutant HSCs in vivo. Mechanistically, DNA hypomethylation-associated overexpression of Txnip in Dnmt3a-mutant HSCs leads to p53 stabilization and upregulation of p21. This preserves the functional potential of Dnmt3a-mutant HSCs through increased quiescence and resistance to IFNγ-induced apoptosis. These data identify a previously undescribed mechanism to explain increased fitness of DNMT3A-mutant clones under hematopoietic stress.
DNMT3A mutations are common variants in clonal hematopoiesis, and recurrent events in blood cancers. Yet the mechanisms by which these mutations provide hematopoietic stem cells a competitive advantage as a precursor to malignant transformation remain unclear. Here, we use inflammatory stress to uncover molecular mechanisms leading to this fitness advantage.See related commentary by De Dominici and DeGregori, p. 178. This article is highlighted in the In This Issue feature, p. 171.
克隆性造血（CH）是指血液系统中特定克隆随年龄增长而发生的扩张，由造血干细胞（HSC）中获得的体细胞突变所导致。大多数CH变异发生在DNMT3A基因中，然而，虽然DNMT3A突变型CH在衰老人群中几乎普遍存在，但缺乏一种统一的分子机制来阐明DNMT3A突变型HSC如何胜过其同类细胞。在这里，我们以干扰素γ（IFNγ）为模型，研究Dnmt3a突变在造血应激下增加HSC适应性的机制。我们发现Dnmt3a突变型HSC能抵抗IFNγ介导的耗竭，并且IFNγ信号传导是Dnmt3a突变型HSC在体内克隆性扩张所必需的。从机制上来说，Dnmt3a突变型HSC中与DNA低甲基化相关的Txnip过表达导致p53稳定和p21上调。这通过增加静止状态和对IFNγ诱导的凋亡的抗性来维持Dnmt3a突变型HSC的功能潜力。这些数据确定了一种先前未描述的机制，以解释DNMT3A突变型克隆在造血应激下适应性增加的现象。
DNMT3A突变是克隆性造血中的常见变异，也是血癌中的复发事件。然而，这些突变作为恶性转化的前体为造血干细胞提供竞争优势的机制仍不清楚。在这里，我们利用炎症应激来揭示导致这种适应性优势的分子机制。见De Dominici和DeGregori的相关评论，第178页。本文在第171页的“本期专题”中被重点介绍。
