Inflammatory Stress Promotes Clonal Expansion of DNMT3A-mutant HSCs

炎症应激促进 DNMT3A 突变型 HSC 的克隆扩增

• 批准号: 10242633
• 负责人: Grant Anthony Challen
• 金额: $ 23.82万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-21 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242633
• 关键词: Acute; Address; Age; Age-Years; Apoptosis; Automobile Driving; Blood; Bone Marrow; Cells; Characteristics; Chronic; Clinical; Clonal Evolution; Clonal Expansion; Clonal Hematopoietic Stem Cell; DNA Modification Methylases; DNA Sequence Alteration; DNMT3a; Data; Development; Disease; Disease Progression; Dysmyelopoietic Syndromes; Environment; Enzymes; Epidemiology; Future; Genes; Genetic; Genetic Models; Genomics; Goals; Growth; Hematology; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Human Cloning; Individual; Infection; Inflammation; Inflammatory; Interferon Type II; Intervention; Kinetics; Light; Longitudinal Studies; Molecular; Monitor; Mutant Strains Mice; Mutate; Mutation; Myeloproliferative disease; Neoplasms; Pathologic; Pathology; Population; Precancerous Conditions; Predisposition; Probability; Recurrence; Research; Resistance; Resources; Retinoblastoma Protein; Risk; Role; Serum; Signal Transduction; Somatic Mutation; Specimen; Stress; Symptoms; System; Time; Variant; Work; cytokine; disorder risk; hazard; hematopoietic stem cell expansion; interest; meetings; microbial; mouse genetics; mouse model; mutant; novel; premalignant; preservation; pressure; prevent; response; stem cell function; success; tool

ABSTRACT Myeloid neoplasms such as myelodysplastic syndromes (MDS) arise from hematopoietic stem cells (HSCs) that acquire genetic mutations which corrupt critical HSC functions. One of the most recurrently mutated genes in these neoplasms is the de novo DNA methyltransferase enzyme DNMT3A. However, DNMT3A mutations can occur in HSCs long before clinical presentation. Recent studies have shown that the HSC clones that predominate with age often contain mutations that are characteristic of myeloid neoplasms. This phenomenon is known as clonal hematopoiesis of indeterminate potential (CHIP), but only a small fraction of individuals with CHIP go on to develop a blood cancer. This suggests that in addition to genetics, there must be other factors that act differently between individuals which select for propagation of HSCs with these mutations. Our lab is interested in identifying factors that change with age which may select for outgrowth of these mutant clones, focusing on inflammation. Our preliminary studies show that stress which induces interferon gamma (IFNg) responses generates an environment that selects for the outgrowth of Dnmt3amutant HSCs. While chronic IFNg signaling is detrimental to normal HSCs, functionality of Dnmt3a-mutant HSCs is preserved in this setting. Thus, we hypothesize that chronic IFNg provides a selective pressure that favors the outgrowth of DNMT3A-mutant HSCs as a mechanism driving CHIP. We propose the resistance of Dnmt3a-mutant HSCs to the deleterious effects of chronic IFNg exposure presents a mechanism through which they can obtain clonal dominance over time as wild-type HSCs become functionally compromised and depleted over time / age. In light of these provocative results, the goal of this application is to understand (A) the cellular and molecular mechanisms through which Dnmt3a-mutant HSCs are resistant to the deleterious effects of IFNg, and (B) the impact of this for progression of pre-malignant HSC expansion to pathological conditions. We propose the following Specific Aims to address these questions; ? The role of IFNg in clonal expansion of Dnmt3a-mutant HSCs ? Mechanisms underlying the differential response of Dnmt3a-mutant HSCs to IFNg ? The impact of inflammation on clonal evolution of Dnmt3a-mutant HSCs The overall goal of this work is to determine the mechanisms by which inflammatory signals promote expansion of Dnmt3a-mutant HSC clones in the bone marrow, which could provide a rationale for development of specific intervening strategies and stratify individuals with CHIP who may be more “at-risk” for disease progression. Approaches to eliminate or selectively inhibit emerging DNMT3A-mutant HSC clones may provide a window for intervention before the mutant cells are able to establish clonal dominance and evolve to disease.

摘要 骨髓瘤如骨髓增生异常综合征（MDS）由造血干细胞（HSC）引起，造血干细胞获得破坏关键HSC功能的基因突变。这些肿瘤中最常发生突变的基因之一是从头DNA甲基转移酶DNMT 3A。然而，DNMT 3A突变可以在临床表现之前很久在HSC中发生。最近的研究表明，随着年龄的增长占主导地位的HSC克隆往往含有髓系肿瘤的特征性突变。这种现象被称为不确定潜能的克隆造血（CHIP），但只有一小部分CHIP患者会发展为血癌。这表明，除了遗传学之外，还必须有其他因素在选择具有这些突变的HSC繁殖的个体之间起不同的作用。我们的实验室有兴趣确定随年龄变化的因素，这些因素可能会选择这些突变克隆的产物，重点是炎症。我们的初步研究表明，诱导干扰素γ（IFNg）反应的应激产生了一个选择Dnmt 3突变型HSC生长的环境。虽然慢性IFNg信号传导对正常HSC是有害的，但Dnmt 3a突变型HSC的功能性在这种情况下得以保留。因此，我们假设慢性IFNg提供了一种选择性压力，有利于DNMT 3A突变型HSC的生长，作为驱动CHIP的机制。我们提出Dnmt 3a突变型HSC对慢性IFNg暴露的有害影响的抗性呈现了一种机制，通过该机制，它们可以随着时间的推移获得克隆优势，因为野生型HSC随着时间/年龄的推移变得功能受损和耗尽。鉴于这些激发性结果，本申请的目标是理解（A）Dnmt 3a突变型HSC对IFNg的有害作用具有抗性的细胞和分子机制，和（B）这对恶化前HSC扩增进展至病理状况的影响。我们提出以下具体目标来解决这些问题： ?干扰素Ng在Dnmt 3a突变肝星状细胞克隆扩增中的作用 ? Dnmt 3a突变的HSC对IFNg的差异反应机制 ?炎症对Dnmt 3a突变型肝星状细胞克隆进化的影响 这项工作的总体目标是确定炎症信号促进骨髓中Dnmt 3a突变型HSC克隆扩增的机制，这可以为开发特定干预策略提供理论基础，并对CHIP患者进行分层，这些患者可能更有疾病进展的“风险”。消除或选择性抑制新出现的DNMT 3A突变HSC克隆的方法可以在突变细胞能够建立克隆优势并演变为疾病之前提供干预的窗口。