Research Center, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada; Department of Medicine, Université de Montréal, Montreal, Québec, Canada.
Research Center, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.
Exp Hematol. 2020 Mar;83:2-11. doi: 10.1016/j.exphem.2020.01.008. Epub 2020 Jan 28.
The history of clonal hematopoiesis (CH) research is punctuated by several seminal discoveries that have forged our understanding of cancer development. The clever application of the principle of random X-chromosome inactivation (XCI) in females led to the development of the first test to identify clonal derivation of cells. Initially limited by a low level of informativeness, the applicability of these assays expanded with differential methylation-based assays at highly polymorphic genes such as the human androgen receptor (HUMARA). Twenty years ago, the observation that skewing of XCI ratios increases as women age was the first clue that led to the identification of mutations in the TET2 gene in hematologically normal aging individuals. In 2014, large-scale genomic approaches of three cohorts allowed definition of CH, which was reported to increase the risk of developing hematologic cancers and cardiovascular diseases. These observations created a fertile field of investigation aimed at investigating the etiology and consequences of CH. The most frequently mutated genes in CH are DNMT3A, TET2, and ASXL1, which have a role in hematopoietic stem cell (HSC) development and self-renewal. These mutations confer a competitive advantage to the CH clones. However, the penetrance of CH is age dependent but incomplete, suggesting the influence of extrinsic factors. Recent data attribute a modest role to genetic predisposition, but several observations point to the impact of a pro-inflammatory milieu that advantages the mutated clones. CH may be a barometer of nonhealthy aging, and interventions devised at curbing its initiation or progression should be a research priority.
克隆性造血 (CH) 研究的历史充满了几个开创性的发现，这些发现推动了我们对癌症发展的理解。巧妙地应用随机 X 染色体失活 (XCI) 原理在女性中导致了第一个识别细胞克隆来源的测试的发展。最初这些检测的应用受到限制，信息量较低，但随着在高度多态性基因（如人类雄激素受体 (HUMARA)）上基于差异甲基化的检测的应用，其适用性得到了扩展。二十年前，观察到 XCI 比例的倾斜随着女性年龄的增长而增加，这是第一个线索，导致在血液学正常衰老个体中鉴定出 TET2 基因突变。2014 年，三个队列的大规模基因组方法允许定义 CH，据报道 CH 增加了发展血液癌症和心血管疾病的风险。这些观察结果为调查 CH 的病因和后果创造了一个富有成效的研究领域。CH 中最常突变的基因是 DNMT3A、TET2 和 ASXL1，它们在造血干细胞 (HSC) 发育和自我更新中起作用。这些突变赋予 CH 克隆竞争优势。然而，CH 的外显率随年龄而变化但不完全，这表明外在因素的影响。最近的数据认为遗传易感性起着适度的作用，但有几个观察结果表明促炎环境的影响有利于突变克隆。CH 可能是不健康衰老的晴雨表，抑制其起始或进展的干预措施应成为研究重点。
