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

项目总结/摘要 年龄是癌症最明确的危险因素之一。由于癌症的发病率随着年龄的增长而增加， 癌症在中年（45-64岁）开始更快地上升，可被认为是与年龄有关的疾病。 最近的研究已经确定了年龄依赖性体细胞突变，包括在癌症起始中起作用的等位基因， in a spectrum光谱of human人tissues组织.在造血系统中，这被称为克隆造血（CH）， 最常见的是由表观遗传调节因子DNMT 3A、TET 2和ASXL 1的突变引起的。 造血干细胞和祖细胞（HSPC）区室。衰老过程如何促进克隆选择， 然而，对于CH向急性髓性白血病（AML）的扩展和转化的认识很少。长期 这项研究的目的是了解衰老促进转化的机制， 血液恶性肿瘤。本提案的总体目标是阐明 在衰老过程中观察到的炎症增加促进CH突变型HSPC的扩增， 这种适应性优势是由改变的表观遗传调节提供的，表观遗传调节是以下因素的直接结果： CH突变。初步数据显示CH突变体HSPC具有更有效的选择性优势， 与年轻小鼠相比，老年小鼠发生更快的恶性转化。机械地，增加 老年小鼠中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-突变型HSPCs伴老化。这些数据支持了一个中心假设，即衰老相关的炎症是 选择压力有利于CH-突变型HSPC扩增和恶性转化， CH突变引起的扩增、表观遗传改变和转化风险取决于 持续CH突变等位基因表达。本项目将采用细胞和分子生物学方法， 小鼠与使用原代人CH样品的研究相结合，以实现以下特定目的：AIM 1. 确定衰老背景下克隆性造血扩增和白血病转化的程度 是由于炎症;和AIM 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生的风险。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如何 在老化过程中共谋扩大，进化和转化CH突变克隆。拟议研究 技术上是创新的，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型小鼠模型， 研究CH突变等位基因在克隆扩增、表观遗传学改变和白血病中依赖性 转型这项研究意义重大，因为了解衰老的机制有助于 克隆扩增和转化将为靶向克隆的有效治疗策略提供见解。 进化，减弱由克隆扩张促进的病理生理学，并阻断恶性转化。

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.