Clonal Hematopoiesis: Getting to the Heart of the Problem With Clone Size.-猫眼课题宝

克隆造血：触及克隆大小问题的核心。

DOI：

10.1016/j.jchf.2023.12.009

发表时间：

2024

期刊：

JACC. Heart failure

影响因子：

通讯作者：

中科院分区：

文献类型：

作者：

Walsh,Kenneth;Cochran,JesseD;Evans,MeganA

一种与年龄相关的疾病，其中一部分成熟血细胞来源于单一优势造血干细胞（HSC）克隆。这种现象可以由HSC内的体细胞驱动突变引起，这为突变的HSC提供了竞争优势，从而促进了其异常扩张。患有CH的个体通常在血液恶性肿瘤中反复突变的基因亚群中存在序列变异，如DNMT3A、TET2和ASXL1。尽管处于癌前状态，但大多数CH患者从未经历过血癌；因此，CH通常被称为不确定电位克隆造血（CHIP）。随着新一代测序技术的最新进展，我们现在能够灵敏地检测小CH克隆，发现CH随着年龄的增长几乎无处不在。虽然CH最初被认为是一种良性的年龄相关现象，但流行病学和实验工作表明，CH是许多年龄相关疾病的关键因素，通常通过促炎过程。CH在心力衰竭（HF）中的作用已被充分证实。在表型良好的队列中，无论病因如何，缺血性心衰、保留射血分数的心力衰竭（HFpEF）和降低射血分数的心力衰竭（HFrEF）患者的CH与较差的预后相关。1-3然而，在占所有心肌病40%的非缺血性扩张型心肌病（DCM）中，缺乏强有力的研究来研究CH的作用。DCM是心衰的一种形式，其特征是心室壁扩大和减弱，导致收缩功能障碍。值得注意的是，这些功能和结构的改变不是由高血压、瓣膜疾病或冠状动脉疾病引起的。遗传遗传占DCM病例的25%至50%，获得性病例可能由感染或自身免疫性疾病引起的炎症引起；暴露于药物、化学物质或毒素中；或者是代谢紊乱。获得性DCM与炎症之间有很强的联系；因此，我们有理由怀疑CH可能在DCM预后恶化中起作用。在这一期的《JACC：心力衰竭》中，Sikking等4报道了他们对这一假说的调查，发现DCM和CH患者确实表现出更严重的心脏和全因死亡率。在该研究中，在门诊会诊期间招募了520例DCM患者，并通过单分子分子倒置探针（smMIP）技术对外周血样本进行超灵敏DNA测序，检测出变异等位基因频率（VAFs）低至0.01%的CH克隆，对应于0.02%的细胞携带CH序列变异。在这种smMIP技术中，每个reads都有一个特定的分子标记序列和样本索引序列，可以分别引用它们的原始DNA分子和样本。真正的变异在具有相同分子标记序列和样本索引序列的所有reads中保持序列变异。为了验证这些变体调用，

age-associated condition whereby a proportion of mature blood cells originate from a single dominant hematopoietic stem cell (HSC) clone. This phenomenon can arise from a somatic driver mutation within an HSC, which provides the mutant HSC with a competitive advantage and consequently facilitates its aberrant expansion. Individuals with CH often harbor sequence variations in a subset of genes recurrently mutated in hematologic malignancies, such as DNMT3A, TET2, and ASXL1. Despite the premalignant state, most individuals with CH never experience a blood cancer; thus, CH is often referred to as clonal hematopoiesis of indeterminate potential (CHIP). With recent advances in next-generation sequencing technologies, we are now able to sensitively detect small CH clones, finding that CH becomes a nearly ubiquitous phenomenon with advanced age. Although CH was initially believed to be a benign age-related phenomenon, epidemiologic and experimental work has demonstrated that CH is a key contributor to numerous age-associated diseases, typically through proinflammatory processes. The role of CH has been well documented in heart failure (HF). In well-phenotyped cohorts, CH has been associated with worse prognosis in patients with ischemic HF, heart failure with preserved ejection fraction (HFpEF), and heart failure with a reduced ejection fraction (HFrEF) irrespective of etiology. 1-3 However, there is a scarcity of well-powered studies examining the role of CH in nonischemic dilated cardiomyopathy (DCM), which accounts for w40% of all cardiomyopathies. DCM is a form of HF characterized by enlarged and weakened ventricular walls, leading to systolic dysfunction. Notably, these functional and structural changes are not attributable to hypertension, valvular disease, or coronary artery disease. Whereas genetic transmission represents w25% to 50% of DCM cases, acquired cases may be driven by inflammation caused by infections or autoimmune disease; by exposure to drugs, chemicals, or toxins; or by metabolic disturbances. There is a strong connection between acquired DCM and inflammation; thus, it is reasonable to suspect that CH could play a role in worsening DCM prognosis.In this issue of JACC: Heart Failure, Sikking et al 4 report their investigation of this hypothesis, uncovering that indeed, patients with DCM and CH exhibit worse cardiac and all-cause mortality. In that study, 520 patients with DCM were recruited during outpatient consultation, and ultrasensitive DNA sequencing via single-molecule molecular inversion probe (smMIP) technology was used on peripheral blood samples to detect CH clones with variant allele frequencies (VAFs) as low as 0.01%, corresponding to 0.02% of cells harboring a CH sequence variation. In this smMIP technology, each read possesses a specific molecular tag sequence and sample index sequence that allows reads to be referenced to their original DNA molecule and sample, respectively. True variants will maintain a sequence variation in all reads with the same molecular tag sequence and sample index sequence. To verify these variant calls,

Clonal Hematopoiesis: Getting to the Heart of the Problem With Clone Size.

克隆造血：触及克隆大小问题的核心。

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