Role of IL-10R signaling in inflammation induced exhaustion of HSC and emergence of JAK2V617F clonal hematopoiesis

IL-10R信号传导在炎症诱导的HSC耗竭和JAK2V617F克隆造血的出现中的作用

基本信息

批准号：
10707093
负责人：
Angela Goffredo Fleischman
金额：
$ 22.43万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-25 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707093
关键词：
Acceleration Acetylcysteine Affect Age Aging Agonist Anti-Inflammatory Agents Antioxidants Attention Biological Markers Blood Bone Marrow Bone Marrow Stem Cell Cell Cycle Cells ChIP-seq Chronic Clinical Trials Clonal Hematopoietic Stem Cell Cytokine Receptors Cytotoxic Chemotherapy DNA Methylation DNA sequencing DNMT3a Data Development Endowment Exposure to Family Family history of Family member Family-Based Registry Gene Expression Gene Expression Profiling Genes Genetic Hematologic Neoplasms Hematology Hematopoiesis Hematopoietic Hematopoietic stem cells Human Inflammation Inflammatory Interleukin-10 Ligands Link Lipopolysaccharides Malignant - descriptor Methylation Modeling Mus Mutation Myeloproliferative disease Oxidative Stress Pathway interactions Patients Persons Phenotype Populations at Risk Predictive Value Predisposition Prevalence Prevention trial Production Proliferating Reactive Oxygen Species Recombinant Interleukin-10 Recording of previous events Regulation Resistance Role Screening procedure Signal Transduction Sorting Stress TLR4 gene TNF gene Testing Therapeutic Toll-like receptors Translating Transplantation Wild Type Mouse Work aged aging population biobank cell type cytokine exhaustion experimental study fitness hematopoietic stem cell emergence hematopoietic stem cell quiescence member methylation pattern monocyte mosaic mutant negative affect peripheral blood pharmacologic preservation prevent progenitor response stem stem cell function stressor transcriptome sequencing

项目摘要

Revised Project Summary Age and chronic inflammatory stress drive the emergence of mutant bone marrow stem cells that can lead to specific hematologic malignancy associated mutations allow HSC to resist specific stressors could be leveraged toward therapies aimed at neutralizing the selective advantage of the malignant clone. We have recently found that patients with myeloproliferative neoplasm (MPN) have a dampened response to the anti-inflammatory cytokine IL-10 and this leads to persistent production of the inflammatory cytokine TNFα. In a murine Jak2V617F MPN model, pharmacologic blockade of IL-10R signaling enhances the selective advantage of Jak2V617F mutant cells. The objective of this project is to define how JAK2V617F mutant HSC gain a selective advantage over wild-type (WT) HSC when IL-10R is blocked. Our central hypothesis is that dampened IL-10R signaling creates an inflammatory state that negatively affects WT but not JAK2V617F mutant HSC, thus endowing JAK2V617F mutant cells a selective advantage. Moreover, we hypothesize that dampened IL-10R signaling is an intrinsic feature of those predisposed to acquire MPN. In Aim 1 we will determine the prevalence of an IL-10 resistance phenotype among MPN families. We have found that MPN patients display an inability to respond to IL-10, which we term the “IL-10 resistance phenotype”. However, cases with a family history of MPN have not been systematically evaluated for the phenotype, nor have unaffected family members. We will determine the prevalence of the IL-10 resistance phenotype in affected and unaffected members of our growing MPN family registry which currently contains 53 MPN families. In Aim 2 we will identify the genetic basis for blunted IL-10R signaling in MPN. We will perform targeted DNA sequencing and gene expression profiling (i.e., RNA-seq, ChIP-seq, and differential DNA methylation analysis) to identify the underlying mechanism responsible for dampened IL-10 signaling in MPN. Using sorted peripheral blood monocytes we will use Illumina Infinium MethylationEPIC chips to determine if MPN patients and unaffected family members with blunted IL-10 signaling have differential methylation of IL-10R signaling genes. Gene expression profiling will be performed in parallel to determine if the methylation pattern accurately predicts gene expression. We will also perform targeted DNA sequencing, focusing on cytokine receptor pathway genes, and paying close attention to any genes found to have differential methylation and/or expression, to identify the genetic basis for blunted IL-10 signaling in MPN patients.

修订后的项目摘要年龄和慢性炎症应激促使突变骨髓干细胞的出现，这些突变可导致特定的血液恶性肿瘤，相关突变使造血干细胞能够抵抗特定的应激源，可用于旨在中和恶性克隆的选择性优势的治疗。骨髓增生性肿瘤 (MPN) 患者对抗炎细胞因子 IL-10 的反应减弱，这导致小鼠 Jak2V617F 持续产生炎性细胞因子 TNFα。 MPN 模型，IL-10R 信号传导的药理阻断增强了 Jak2V617F 突变细胞的选择性优势该项目的目的是确定当 IL-10R 被阻断时，JAK2V617F 突变型 HSC 如何获得相对于野生型 (WT) HSC 的选择性优势。我们的中心假设是，IL-10R 信号传导减弱会产生炎症状态，对 WT 产生负面影响，但不会对 JAK2V617F 突变体 HSC 产生负面影响，从而赋予JAK2V617F 突变细胞具有选择性优势，此外，我们发现 IL-10R 信号传导减弱是那些易于获得 MPN 的细胞的固有特征，我们将确定 MPN 家族中 IL-10 耐药表型的流行情况。 MPN 患者对 IL-10 表现出无反应，我们称之为“IL-10 耐药表型”。然而，具有 MPN 家族史的病例尚未对该表型进行系统评估。我们将确定我们不断增长的 MPN 家族登记中受影响和未受影响的成员中 IL-10 耐药表型的患病率，该登记目前包含 53 个 MPN 家族。在目标 2 中，我们将确定 IL-10R 信号减弱的遗传基础。 MPN。我们将进行靶向 DNA 测序和基因表达谱分析（即 RNA-seq、ChIP-seq 和差异 DNA 甲基化分析），以确定导致抑制的潜在机制。 MPN 中的 IL-10 信号传导。我们将使用 Illumina Infinium MmethylationEPIC 芯片来确定 IL-10 信号传导减弱的 MPN 患者和未受影响的家庭成员是否具有 IL-10R 信号传导基因的差异甲基化。同时，为了确定甲基化模式是否准确预测基因表达，我们还将进行靶向 DNA 测序，重点关注细胞因子受体途径基因，并密切关注任何发现有差异的基因。甲基化和/或表达，以确定 MPN 患者 IL-10 信号减弱的遗传基础。