Assessing the Interplay Between Inflammatory Signaling and Epigenetic Dysregulation in Age-associated Clonal Hematopoiesis and Leukemia Initiation

评估炎症信号传导与表观遗传失调在年龄相关克隆造血和白血病起始中的相互作用

• 批准号: 10659254
• 负责人: Ross L Levine
• 金额: $ 51.55万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659254
• 关键词: Acute Myelocytic Leukemia; Age; Aging; Alleles; Attenuated; Automobile Driving; Biological; Blood; CSF1 gene; Cell Compartmentation; Clonal Evolution; Clonal Expansion; Coculture Techniques; Complex; Credentialing; Cytokine Signaling; DNMT3a; DNMT3a mutation; Data; Dependence; Disease; Engineering; Epigenetic Process; Functional disorder; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; Human; Incidence; Individual; Inflammaging; Inflammation; Inflammation Mediators; Inflammatory; Intercept; Knock-in Mouse; Link; Literature; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Mus; Mutation; Patients; Phenotype; Process; Production; Public Health; Research; Risk; Risk Factors; Role; Sampling; Signal Transduction; Somatic Mutation; System; Testing; Therapeutic Studies; Therapeutic Use Study; Tissues; age related; aged; cancer initiation; cancer risk; cytokine; epigenetic regulation; fitness; functional genomics; hematopoietic stem cell expansion; high risk; human tissue; in vivo; innovation; insight; leukemia; leukemic transformation; middle age; mouse model; mutant; new therapeutic target; novel; pre-clinical; pressure; prevent; response; small molecule inhibitor; stem cell survival; therapeutically effective

PROJECT SUMMARY/ABSTRACT Age is one of the most clearly defined risk factors for cancer. As the incidence of cancer increases with age, rising more rapidly beginning in mid-life (ages 45-64 years), cancer can be considered an age-related disease. Recent studies have identified age-dependent somatic mutations, including alleles with a role in cancer initiation, in a spectrum of human tissues. In the hematopoietic system this is termed clonal hematopoiesis (CH) and is most commonly caused by mutations in the epigenetic regulators DNMT3A, TET2, and ASXL1 within the hematopoietic stem and progenitor cell (HSPC) compartment. How the aging process promotes clonal selection, expansion, and transformation from CH to acute myeloid leukemia (AML) is poorly understood. The long-term goal of this research is to understand the mechanisms by which aging promotes transformation causing hematologic malignancies. The overall objective of this proposal is to elucidate the mechanisms by which increased inflammation observed during aging promotes expansion of CH-mutant HSPCs, and the extent to which this fitness advantage is provided by altered epigenetic regulation occurring as a direct consequence of CH mutations. Preliminary data show that CH-mutant HSPCs have a more potent selective advantage and undergo more rapid malignant transformation in aged compared to young mice. Mechanistically, increased inflammation in aged mice is a driver of this phenotype and epigenetic alterations are found to accumulate in CH-mutant HSPCs with aging. These data support the central hypothesis that aging-associated inflammation is a selective pressure favoring CH-mutant HSPC expansion and malignant transformation, and that clonal expansion, epigenetic alterations, and risk of transformation caused by CH mutations are dependent upon sustained CH-mutant allele expression. This project will use cellular and molecular biological approaches in aged mice integrated with studies using primary human CH samples to achieve the following specific aims: AIM 1. Determine the extent to which clonal hematopoietic expansion and leukemic transformation in the aging context is due to inflammation; and AIM 2. Determine the mechanisms by which, and extent to which, reversion of a CH mutation during aging alters clonal evolution and risk of leukemia initiation. The proposed research is conceptually innovative because it is the first to determine how inflammation and epigenetic dysregulation conspire during the aging process to expand, evolve and transform CH-mutant clones. The proposed research is technically innovative as it incorporates novel co-culture systems and therapeutic studies to assess key inflammatory drivers, as well as a novel murine model with CH-mutant induction and reversion capabilities to investigate CH mutant allele dependencies in clonal expansion, epigenetic alterations, and leukemic transformation. This study is significant because understanding the mechanisms by which aging contributes to clonal expansion and transformation will provide insights into effective therapeutic strategies targeting clonal evolution, attenuate pathophysiology promoted by clonal expansion, and intercept malignant transformation.

项目概要/摘要 年龄是最明确的癌症危险因素之一。由于癌症的发病率随着年龄的增长而增加， 癌症从中年（45-64岁）开始上升得更快，可以被认为是一种与年龄相关的疾病。 最近的研究发现了年龄依赖性体细胞突变，包括在癌症发生中发挥作用的等位基因， 在一系列人体组织中。在造血系统中，这被称为克隆造血 (CH)，并且是 最常见的是由表观遗传调节因子 DNMT3A、TET2 和 ASXL1 的突变引起 造血干细胞和祖细胞 (HSPC) 室。衰老过程如何促进克隆选择， 人们对 CH 向急性髓系白血病 (AML) 的扩展和转化知之甚少。长期来看 这项研究的目标是了解衰老促进转化的机制 血液系统恶性肿瘤。该提案的总体目标是阐明机制 衰老过程中观察到的炎症增加促进了 CH 突变型 HSPC 的扩增，并且其程度 这种适应性优势是通过改变表观遗传调控来提供的，而表观遗传调控是 CH突变。初步数据表明，CH突变型HSPC具有更强大的选择性优势， 与年轻小鼠相比，老年小鼠的恶性转化速度更快。机械上，增加了 老年小鼠的炎症是这种表型的驱动因素，并且发现表观遗传改变在 CH 突变 HSPC 随衰老。这些数据支持了一个中心假设：与衰老相关的炎症是 有利于 CH 突变体 HSPC 扩增和恶性转化的选择压力，并且该克隆 CH 突变引起的扩张、表观遗传改变和转化风险取决于 持续的 CH 突变等位基因表达。该项目将使用细胞和分子生物学方法治疗老年人 小鼠与使用原始人类 CH 样本的研究相结合，以实现以下特定目标：AIM 1。 确定衰老背景下克隆造血扩张和白血病转化的程度 是由于炎症引起的；和目标 2. 确定 CH 恢复的机制和程度 衰老过程中的突变会改变克隆进化和白血病发生的风险。拟议的研究是 概念上具有创新性，因为它是第一个确定炎症和表观遗传失调如何发生的 在衰老过程中合谋扩大、进化和转化CH突变体克隆。拟议的研究 在技​​术上具有创新性，因为它结合了新颖的共培养系统和治疗研究来评估关键 炎症驱动因素，以及具有 CH 突变诱导和逆转能力的新型小鼠模型 研究克隆扩增、表观遗传改变和白血病中 CH 突变等位基因依赖性 转变。这项研究意义重大，因为了解衰老导致的机制 克隆扩增和转化将为针对克隆的有效治疗策略提供见解 进化，减弱克隆扩张促进的病理生理学，并阻止恶性转化。