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: 10654280
• 负责人: Grant Anthony Challen
• 金额: $ 44.08万
• 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 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654280
• 关键词: Age; Autoimmune Diseases; Automobile Driving; Biological Assay; Blood; Bone Marrow; Bone Regeneration; Bone remodeling; Candidate Disease Gene; Cell division; Cells; Characteristics; Chronic; Clinical; Clonal Expansion; Clonal Hematopoietic Stem Cell; Collaborations; DNA Modification Methylases; DNA Sequence Alteration; DNMT3a; DNMT3a mutation; Data; Development; Disease; Disease Progression; Dysmyelopoietic Syndromes; Elderly; Environment; Enzymes; Funding; Future; Gene Frequency; Genes; Genetic; Genomics; Genotype; Goals; Growth; Hematological Disease; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; High Prevalence; Human; Individual; Infection; Inflammation; Inflammatory; Interferon Type II; Intervention; Life; Malignant Neoplasms; Modeling; Molecular; Mutant Strains Mice; Mutate; Mutation; Myeloproliferative disease; Neoplasms; Pathway interactions; Patients; Persons; Process; Production; Publishing; Recurrence; Resistance; Resources; Risk; Role; Serum; Signal Transduction; Stress; Symptoms; System; T cell infiltration; T-Lymphocyte; Testing; Time; Ulcerative Colitis; Up-Regulation; Variant; Work; cancer prevention; cohort; conditioning; cytokine; driver mutation; environmental stressor; experimental study; fitness; genetic variant; hematopoietic stem cell self-renewal; high risk; high risk population; human old age (65+); in vivo; interest; microbial; mouse model; mutant; novel; pharmacologic; preservation; pressure; prevent; recruit; response; risk mitigation; stem cell function; stem cells; therapy development; tool; virtual

ABSTRACT Blood diseases 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 (CH), but only a small fraction of individuals with CH go on to develop a blood disease. This suggests that in addition to genetics, there must be other factors which act differently between individuals that select for propagation of HSCs with these mutations. Our lab is interested in identifying factors that change with age which may provide selective pressures for these mutant clones, focusing on inflammation. The prior funding period identified interferon gamma (IFNg) as an environmental stressor that selects for the outgrowth of Dnmt3a-mutant HSCs. While chronic IFNg signaling is detrimental to normal HSCs, functionality of Dnmt3a-mutant HSCs is preserved in this setting, presenting a mechanism whereby HSCs with these mutations gain clonal dominance in settings of inflammation. New data generated in our lab show that Dnmt3a-mutant HSCs are not only resistant to the detrimental effects of IFNg in vivo, but also the mutant clones produce more IFNg themselves in response to inflammation. This is associated with increased Cxcl9 expression from the mutant clones and T-cell infiltration into the BM. These observations form the scientific premise for this renewal application. We hypothesize that IFNg production by Dnmt3a-mutant clones suppresses other HSC genotypes and remodels the niche through T-cell infiltration to further reinforce their competitive advantage. We propose the following Specific Aims to investigate these questions;  Determine if IFNg production from Dnmt3a-mutant clones exacerbates their competitive advantage.  Determine if Dnmt3a-mutant clones remodel the BM niche.  Examine the cellular and molecular mechanisms by which Dnmt3a-mutant cells are hypersensitive to IFNg. The overall goal of this work is to determine the mechanisms by which inflammatory signals promote clonal expansion of Dnmt3a-mutant HSCs in the bone marrow. Approaches to eliminate or selectively inhibit emerging DNMT3A-mutant HSC clones from high-risk CH+ individuals may provide a window for intervention before the mutant cells are able to establish clonal dominance and evolve to fulminant disease.

摘要 骨髓增生异常综合征（MDS）等血液疾病是由造血干细胞（HSC）引起的。 获得破坏关键HSC功能的基因突变。其中一个最反复突变的 这些肿瘤中的基因是从头DNA甲基转移酶DNMT 3A。DNMT3A 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，HSC 随着年龄增长而占优势的克隆通常含有髓样肿瘤特征性的突变。这 这种现象被称为克隆造血（CH），但只有一小部分患有CH的个体会继续 患上血液病这表明，除了遗传因素，还必须有其他因素起作用。 不同的个体选择这些突变的HSC的繁殖。我们的实验室很感兴趣 在鉴定可能为这些突变克隆提供选择压力的随年龄变化的因素时， 关注炎症前一个资助期将干扰素γ（IFNg）确定为环境干扰素。 选择Dnmt3a突变型HSC生长的应激因子。虽然慢性IFNg信号传导对 在正常的HSC中，Dnmt3a突变的HSC的功能在这种情况下被保留，提出了一种机制， 从而具有这些突变的HSC在炎症环境中获得克隆优势。生成的新数据 我们的实验室表明，Dnmt3a突变的HSC不仅在体内对IFNg的有害作用有抵抗力， 而且突变克隆自身响应炎症产生更多IFNg。这是与 增加了突变克隆的Cxcl9表达和T细胞向BM的浸润。这些观察形成 这一更新申请的科学前提。我们假设Dnmt3a突变体产生IFNg， 克隆抑制其他HSC基因型，并通过T细胞浸润重塑生态位，以进一步增强HSC的免疫功能。 他们的竞争优势。我们提出以下具体目标来研究这些问题： 确定来自Dnmt3a突变克隆的IFNg产生是否加剧了它们的竞争性 优势 确定Dnmt3a突变克隆是否重塑BM生态位。 研究Dnmt3a突变细胞的细胞和分子机制， 对IFNg过敏 这项工作的总体目标是确定炎症信号促进克隆形成的机制。 Dnmt3a突变型HSC在骨髓中的扩增。消除或有选择地抑制 来自高风险CH+个体的新兴DNMT3A突变HSC克隆可能提供干预窗口 在突变细胞能够建立克隆优势并进化成暴发性疾病之前。