PDF(Pubmed)
Abstract：
Recent genome-wide studies have revealed that aging or chronic inflammation can cause clonal expansion of cells in normal tissues. Clonal hematopoiesis has been the most intensively studied form of clonal expansion in the last decade. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related phenomenon observed in elderly individuals with no history of hematological malignancy. The most frequently mutated genes in CHIP are DNMT3A, TET2, and ASXL1, which are associated with initiation of leukemia. Importantly, CHIP has been the focus of a number of studies because it is an independent risk factor for myeloid malignancy, cardiovascular disease (CVD), and all-cause mortality. Animal models recapitulating human CHIP revealed that CHIP-associated mutations alter the number and function of hematopoietic stem and progenitor cells (HSPCs) and promote leukemic transformation. Moreover, chronic inflammation caused by infection or aging confers a fitness advantage to the CHIP-associated mutant HSPCs. Myeloid cells, such as macrophages with a CHIP-associated mutation, accelerate chronic inflammation and are associated with increased levels of inflammatory cytokines. This positive feedback loop between CHIP and chronic inflammation promotes development of atherosclerosis and chronic heart failure and thereby increases the risk for CVD. Notably, HSPCs with a CHIP-associated mutation may alter not only innate but also acquired immune cells. This suggests that CHIP is involved in the development of solid cancers or immune disorders, such as aplastic anemia. In this review, we provide an overview of recent findings on CHIP. We also discuss potential interventions for treating CHIP and preventing myeloid transformation and CVD progression.
摘要：
最近的全基因组研究表明，衰老或慢性炎症可导致正常组织中细胞的克隆扩增。在过去的十年中，克隆造血一直是研究最深入的克隆扩增形式。不确定潜能的克隆造血（CHIP）是在没有血液系统恶性肿瘤病史的老年人中观察到的与年龄有关的现象。CHIP中最常见的突变基因是DNMT3A，TET2和ASXL1与白血病的发生有关。重要的是,CHIP一直是许多研究的焦点，因为它是髓系恶性肿瘤的独立危险因素。心血管疾病（CVD），和全因死亡率。人类CHIP的动物模型显示，与CHIP相关的突变会改变造血干细胞和祖细胞（HSPC）的数量和功能，并促进白血病转化。此外，由感染或衰老引起的慢性炎症赋予CHIP相关突变HSPC适应性优势.髓系细胞,如具有CHIP相关突变的巨噬细胞，加速慢性炎症，并与炎症细胞因子水平升高有关。CHIP和慢性炎症之间的这种正反馈回路促进了动脉粥样硬化和慢性心力衰竭的发展，从而增加了CVD的风险。值得注意的是,具有CHIP相关突变的HSPC不仅可以改变先天免疫细胞，还可以改变获得性免疫细胞。这表明CHIP参与实体癌或免疫疾病的发展，如再生障碍性贫血。在这次审查中,我们概述了芯片的最新发现。我们还讨论了治疗CHIP和预防髓样转化和CVD进展的潜在干预措施。
