Modifiable Drivers of Expansion and Malignant Transformation from Clonal Hematopoiesis

项目总结/摘要 克隆性造血（CH）是一种与年龄相关的癌前病变，其中造血干细胞的后代 在大约20个基因中具有体细胞突变的干细胞和祖细胞（HSPC）主导了 外周血虽然CH可以持续数十年而没有明显的健康后果，但它与 增加血液恶性肿瘤风险以及全因死亡率。外部条件有利于 特定的克隆可以将无症状的CH携带者与那些进展为疾病的CH携带者分开;然而， 可以改变以影响CH及其后遗症的危险因素在很大程度上是未知的。这个项目的总体目标是 计划，有三个互动项目和两个核心，是确定可修改的风险因素CH相关 HSPC扩增和随后的恶性转化，长期来看可能发展为癌症 预防战略。我们的计划的一个主要特点是使用新的小鼠模型来模拟CH和测试 导致克隆扩张和恶性的机制。此外，我们的计划利用来自 社区中的特殊动脉粥样硬化风险（ARIC）研究-该研究跟踪了9，500多个不同的 参与者（27%黑人，55%女性）超过30年-评估CH和恶性肿瘤的风险在老年人。项目 1在小鼠中建立了CH模型，重点是在表观遗传调节因子（特别是 Dnmt 3a和Tet 2），以确定炎症应激和代谢变化如何促进扩张，包括 克隆人之间的合作和恶性转化。项目2关注CH伴DNA损伤 与DDR相关的基因突变，以及暴露于化疗和化疗引起的遗传毒性应激 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都在探索潜力 抑制克隆扩张的干预措施。项目3分析了炎症和DNA的贡献 在ARIC队列中暴露于克隆扩增和恶性转化的破坏性暴露， 临床、蛋白质组学、甲基化、全外显子组测序和代谢组学数据已经可用。项目3 还将进行单细胞测序，以确定CH克隆贡献随时间的变化，包括克隆 相互作用，并在外部压力的背景下演变为恶性肿瘤。项目高度 互动，项目1和2反复测试提名的风险因素的因果和机制影响 通过初步研究和项目3，项目3进行额外的分析，以验证结果 由项目1和项目2生成。项目1和2通过共享方法和数据而相互促进。 总之，所有项目将消除CH和恶性肿瘤风险因素的作用。该方案得到支持 由单细胞测序和生物信息学核心和管理核心组成。通过关注可改变的风险 因素，我们可以对血液系统恶性肿瘤的风险进行分层，以告知CH患者的临床指导。 专家团队将临床医生和科学家结合起来，具有长期成功合作的记录。我们一起 将解决这一关系到人类健康和寿命的关键问题。

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.