Modifiable Drivers of Expansion and Malignant Transformation from Clonal Hematopoiesis

项目摘要/摘要 克隆性造血(CH)是一种与年龄相关的癌前状态，在这种情况下，造血细胞的后代 具有约20个基因体细胞突变的干细胞和祖细胞(HSPC)主导着 外周血液。虽然CH可以持续数十年而不会对健康造成明显的影响，但它与 血液系统恶性肿瘤的风险增加，以及全因死亡。有利的外在条件 特定的克隆可以将无症状的CH携带者与进展为疾病的CH携带者区分开来；然而，特定的 可以修改以影响CH及其后遗症的风险因素在很大程度上是未知的。这个项目的总体目标是 该计划由三个互动项目和两个核心组成，旨在确定与CH相关的可修改的风险因素 HSPC扩张和随后的恶变，并着眼于癌症的长期发展 预防策略。我们程序的一个主要特点是使用新的鼠标模型来模拟CH和测试 驱动克隆扩张和恶性转化的机制。此外，我们的程序利用来自 社区中特殊的动脉粥样硬化风险(ARIC)研究-跟踪了9,500多种不同的 受试者(27%黑人，55%女性)年龄在30岁以上--以评估老年人的先天性心脏病和恶性肿瘤风险。项目 1小鼠CH模型，重点是HSPC携带表观遗传调节基因突变(特别是 DNMT3A和TET2)，以确定炎症应激和代谢变化如何促进扩张，包括 克隆人之间的合作，以及恶变。项目2专注于DNA损伤的CH 反应(DDR)相关的基因突变，以及如何暴露于化疗和 吸烟使小鼠的克隆优势和恶性转化成为可能。项目1和项目2都发掘了潜力 抑制克隆扩张的干预措施。项目3分析了炎症和DNA的作用 ARIC队列中对克隆扩张和恶变的破坏性暴露，利用 临床、蛋白质组、甲基化、整个外显子组测序和代谢组学数据已经可用。项目3 还将执行单细胞测序，以确定CH克隆贡献随时间的变化，包括克隆 相互作用，以及在外部应激源的背景下向恶性肿瘤的演变。这些项目都是高度 互动，项目1和2反复测试被提名的风险因素的因果和机械影响 通过初步研究和项目3以及项目3执行附加分析以验证结果 由项目1和项目2生成。项目1和项目2通过共享的方法和数据相互增强。 总而言之，所有项目都将揭示风险因素对慢性肝炎和恶性肿瘤的作用。该计划受支持 由单细胞测序和生物信息学核心和管理核心组成。通过关注可修改的风险 因素，我们可以分层的血液系统恶性肿瘤的风险，为临床指导个人的CH。我们的 专家团队结合了临床医生和科学家成功合作的长期记录。我们在一起 将解决这一对人类健康和长寿至关重要的问题。

Project Summary/Abstract Clonal hematopoiesis (CH) is an age-associated pre-malignant condition in which the progeny of hematopoietic stem and progenitor cells (HSPCs) with somatic mutations in about 20 genes dominate production of the peripheral blood. While CH can persist without apparent health consequences for decades, it is associated with increased risk for hematologic malignancies as well as all-cause mortality. Extrinsic conditions that favor particular clones may separate asymptomatic CH carriers from those that progress to disease; yet, the specific risk factors that can be modified to influence CH and its sequelae are largely unknown. The overall goal of this Program, with three interactive Projects and two Cores, is to identify modifiable risk factors of CH-associated HSPC expansion and subsequent malignant transformation, with a long-term view toward developing cancer prevention strategies. A major feature of our Program is the use of novel mouse models to mimic CH and test mechanisms that drive clone expansion and malignancy. In addition, our Program harnesses data from the exceptional Atherosclerosis Risk in Communities (ARIC) study – which has followed more than 9,500 diverse participants (27% Black, 55% female) over 30 years – to evaluate CH and malignancy risk in older adults. Project 1 models CH in mice, with an emphasis on HSPCs bearing mutations in epigenetic regulators (particularly Dnmt3a and Tet2), to determine how inflammatory stress and metabolic changes promote expansion, including cooperation between clones, and malignant transformation. Project 2 focuses on CH with DNA Damage Response (DDR)-associated gene mutations, and how exposure to genotoxic stress from chemotherapy and smoking enables clonal dominance and malignant transformation in mice. Both Projects 1 and 2 explore potential interventions to suppress clone expansion. Project 3 analyzes the contribution of inflammation and DNA damaging exposures to clonal expansion and malignant transformation in the ARIC cohort, capitalizing on clinical, proteomic, methylation, whole exome sequencing, and metabolomic data already available. Project 3 will also perform single cell sequencing to determine changes in CH clonal contribution over time, including clonal interactions, and the evolution to malignancy in the context of external stressors. The Projects are highly interactive, with Projects 1 and 2 iteratively testing the causal and mechanistic influence of risk factors nominated by preliminary studies and by Project 3, and Project 3 performing additional analyses to validate findings generated by Projects 1 and 2. Projects 1 and 2 are mutually enhanced by shared approaches and data. Together, all Projects will deconvolute the role of risk factors to CH and malignancy. The Program is supported by a Single Cell Sequencing and Bioinformatics Core and an Administrative Core. By focusing on modifiable risk factors, we can stratify the risk of hematologic malignancy to inform clinical guidance of individuals with CH. Our expert team combines clinicians and scientists with long track records of successful collaboration. Together we will address this critical problem for human health and longevity.