Modifiable Drivers of Expansion and Malignant Transformation from Clonal Hematopoiesis

克隆造血扩张和恶性转化的可改变驱动因素

• 批准号: 10606550
• 负责人: MARGARET A. GOODELL
• 金额: $ 221.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-08 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606550
• 关键词: Acceleration; Adult; Age; Apoptosis; Atherosclerosis Risk in Communities; Attenuated; Automobile Driving; Bioinformatics; Black race; Blood specimen; Bone Marrow; Cells; Clinical; Clonal Expansion; Clone Cells; Collaborations; Communities; Coupled; DNA Damage; DNA Sequence Alteration; DNMT3a; Data; Development; Disease; Elderly; Ensure; Epigenetic Process; Etiology; Evolution; Exposure to; Female; Gene Mutation; Genes; Genotoxic Stress; Goals; Health; Hematologic Neoplasms; Hematopoiesis; Hematopoietic stem cells; High Fat Diet; Human; Incidence; Individual; Infection; Inflammation; Inflammatory; Infrastructure; Intervention; Longevity; Malignant - descriptor; Malignant Neoplasms; Measures; Metabolic; Methylation; Modeling; Multiomic Data; Mus; Mutation; Obesity; Outcome; Oxidative Stress; Participant; Pathway interactions; Patients; Persons; Precancerous Conditions; Prevention strategy; Production; Proteomics; Publications; Recording of previous events; Records; Recurrence; Research Personnel; Risk; Risk Factors; Role; Sampling; Scientist; Smoking; Somatic Mutation; Stress; Study models; Testing; Time; Validation; Variant; cancer prevention; chemotherapy; cigarette smoking; cohort; epidemiological model; epidemiology study; exome sequencing; genotoxicity; metabolomics; modifiable risk; mortality; mosaic; mouse model; mutant; non-genetic; novel; peripheral blood; premalignant; programs; response; risk mitigation; risk stratification; single cell sequencing; stressor; success; transplant model

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.

项目概要/摘要 克隆性造血（CH）是一种与年龄相关的癌前病变，其中造血细胞的后代 大约 20 个基因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 可以持续数十年而不产生明显的健康后果，但它与 血液系统恶性肿瘤以及全因死亡率的风险增加。有利于的外部条件 特定的克隆可以将无症状的慢性肝炎携带者与那些进展为疾病的携带者区分开来；然而，具体的 可以改变以影响 CH 及其后遗症的危险因素在很大程度上尚不清楚。本次活动的总体目标 该计划包含三个互动项目和两个核心，旨在确定 CH 相关的可改变风险因素 HSPC 扩张和随后的恶性转化，从长远来看会发展为癌症 预防策略。我们计划的一个主要特点是使用新颖的小鼠模型来模拟 CH 并进行测试 驱动克隆扩张和恶性的机制。此外，我们的计划利用来自 杰出的社区动脉粥样硬化风险 (ARIC) 研究 – 该研究跟踪了超过 9,500 项不同的研究 年龄超过 30 岁的参与者（27% 黑人，55% 女性）——评估老年人的 CH 和恶性肿瘤风险。项目 1 小鼠 CH 模型，重点是带有表观遗传调节因子突变的 HSPC（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 克隆之间的合作和恶性转化。项目 2 重点研究伴有 DNA 损伤的 CH 反应（DDR）相关基因突变，以及如何暴露于化疗和化疗引起的基因毒性应激 吸烟会导致小鼠的克隆优势和恶性转化。项目 1 和 2 都探索潜力 抑制克隆扩张的干预措施。项目 3 分析炎症和 DNA 的贡献 ARIC 队列中克隆扩张和恶性转化的破坏性暴露，利用 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，以及在外部压力源的背景下向恶性肿瘤的演变。该项目具有高度 互动，项目 1 和 2 迭代测试指定风险因素的因果和机械影响 通过初步研究和项目 3，项目 3 进行额外分析以验证研究结果 由项目 1 和 2 生成。项目 1 和 2 通过共享方法和数据相互增强。 所有项目将共同阐明风险因素对慢性肝炎和恶性肿瘤的作用。该计划受到支持 由单细胞测序和生物信息学核心以及管理核心组成。通过关注可改变的风险 因素，我们可以对血液恶性肿瘤的风险进行分层，为 CH 患者的临床指导提供信息。我们的 专家团队由具有长期成功合作记录的临床医生和科学家组成。我们一起 将解决人类健康和长寿的这一关键问题。