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

项目摘要/摘要 年龄是最明确定义的癌症风险因素之一。随着癌症发病率随着年龄的增长而增加， 癌症从中年(45岁-)开始上升更快，可以被认为是一种与年龄相关的疾病。 最近的研究已经确定了年龄相关的体细胞突变，包括在癌症发生中起作用的等位基因， 在人体组织的光谱中。在造血系统中，这被称为克隆性造血(CH) 最常见的原因是表观遗传调节子DNMT3A、TET2和ASXL1在 造血干祖细胞(HSPC)室。衰老过程如何促进克隆选择， 从慢性粒细胞白血病向急性髓系白血病(AML)的扩展和转化还知之甚少。长期的 本研究的目的是了解衰老促进转化的机制。 恶性血液病。这项建议的总体目标是阐明通过哪些机制 在衰老过程中观察到的炎症增加促进了CH突变的HSPC的扩张，并且程度 这种适合性优势是由改变的表观遗传调控提供的，这是 CH突变。初步数据显示，CH突变体HSPC具有更强的选择优势 与年轻小鼠相比，老年小鼠经历了更快的恶变。机械上，增加了 老年小鼠的炎症是这种表型的驱动因素，表观遗传改变被发现在 CH-突变型HSPC随年龄增长。这些数据支持这样一个中心假设，即与衰老相关的炎症 一种有利于CH突变型HSPC扩增和恶变的选择压力，以及克隆 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。该项目将在老年人中使用细胞和分子生物学方法 小鼠结合使用原始人CH样本进行的研究，以实现以下特定目标：目标1。 确定在衰老背景下克隆性造血扩张和白血病转化的程度 是由炎症引起的；以及目的2.确定CH逆转的机制和程度 衰老过程中的突变改变了克隆进化和白血病发病的风险。拟议的研究是 概念上的创新，因为它是第一个确定炎症和表观遗传失调 在老化过程中合谋扩大、进化和转化CH突变克隆。拟议的研究 是技术创新的，因为它结合了新的共培养系统和治疗研究，以评估关键 炎症驱动因素，以及具有CH突变诱导和逆转能力的新的小鼠模型 研究克隆性扩张、表观遗传学改变和白血病的CH突变等位基因相关性 转型。这项研究具有重要意义，因为了解衰老对 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，并拦截恶性转化。

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.