The role of inflammation in the regulation of immune response in acute myeloid leukemia

炎症在急性髓系白血病免疫反应调节中的作用

• 批准号: 10729281
• 负责人: Iannis Aifantis
• 金额: $ 57.03万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729281
• 关键词: ATAC-seq; Acute Myelocytic Leukemia; Acute leukemia; Adult; Animal Model; Anti-Inflammatory Agents; Antibodies; Atlases; B-Lymphocytes; B-cell receptor repertoire sequencing; Blast Cell; Bone Marrow; Bone remodeling; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Censuses; Chromatin; Clinical; Clonality; Collection; Coupled; Cytarabine; Data; Daunorubicin; Development; Disease; Disease Progression; Epitopes; Event; Exhibits; Gene Expression; Generations; Genes; Genetic; Genomics; Genotype; Goals; Hematopoietic stem cells; Human; IL1R1 gene; IRAK1 gene; Immune; Immune response; Immune system; Immunocompetent; Inferior; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1; Leukemic Cell; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator; Membrane Proteins; Modeling; Molecular; Mus; Mutate; Mutation; Myeloid Cells; Myeloproliferative disease; Other Genetics; Outcome; Patients; Phenotype; Play; Population; Predisposition; Regimen; Resolution; Risk; Role; Sampling; Signal Transduction; Specificity; Structure; Subgroup; Supporting Cell; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Treatment Protocols; cancer cell; cell transformation; cohort; design; effectiveness testing; exome sequencing; immunoregulation; improved; indexing; inhibitor; insight; leukemia; leukemogenesis; monocyte; mouse model; multiple omics; negative affect; new therapeutic target; novel; prevent; protein expression; response; single cell technology; single-cell RNA sequencing; standard of care; survival outcome; targeted agent; transcriptome; transcriptome sequencing; treatment effect; treatment response; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

Project Summary/Abstract Survival outcomes of acute myeloid leukemia (AML) patients are negatively affected by high inflammation in the bone marrow compared to low inflammation patients within the same molecular subgroup. The overarching goal of our study is to delineate functionally relevant contributors to aberrant inflammation, characterize changes to the inflammatory state longitudinally during different standard-of-care treatment approaches and determine whether targeting inflammation via inhibitors that target the crucial mediators of inflammation can improve treatment response and survival. The proposal was prompted by our recent characterization of inflammation- mediated progression to AML in animal models and the notable cooperation with select mutational backgrounds to promote leukemogenesis; and our notion of distinct cellular remodeling of both leukemic cells and the microenvironment to promote inflammation. We believe that the observed strong negative treatment response and survival association that was independent from other genetic contributors provides an exciting rationale to target aberrant inflammation in AML patients in order to improve treatment response and disease progression. This goal will be achieved by two independent, but complementary Specific Aims. (1) Utilizing our large cohort of 1,600 AML patients who were molecularly and clinically characterized and have a defined inflammatory state, we will characterize those patients with the highest and the lowest inflammation and compare cell state, cell fate and immune response at the single cell level via a comprehensive multi-omic approach. (2) We will track dynamics of inflammatory, immune-regulatory and associated clonal structures during different treatments via the same multi-omic profiling with an integrated approach that first profiles longitudinally collected patient samples with select genotypes during different treatments, followed by patient derived xengraft models of the same patients that will undergo 2 different therapeutic approaches followed by serial profiling, thereby allowing for direct comparison and definitive characterization of the observed changes. Lastly, we will test the effectiveness of anti-inflammatory agents (IL-1 inhibitors) to lower inflammation and prevent the inflammation- associated bone marrow remodeling and inferior treatment response. Together, our results will, for the first time, provide critically needed information to provide a basis for targeting aberrant inflammation in AML patients.

项目概要/摘要 急性髓系白血病 (AML) 患者的生存结果受到全身炎症反应的负面影响 骨髓与同一分子亚组内的低炎症患者相比。总体目标 我们研究的目的是描述异常炎症的功能相关因素，表征变化 在不同标准护理治疗方法期间纵向炎症状态并确定 通过针对炎症关键介质的抑制剂来靶向炎症是否可以改善 治疗反应和生存。该提议是由我们最近对炎症的描述而提出的—— 在动物模型中介导 AML 进展以及与特定突变背景的显着合作 促进白血病发生；以及我们对白血病细胞和 促进炎症的微环境。我们相信观察到的强烈的负面治疗反应 独立于其他遗传因素的生存关联提供了令人兴奋的理由 针对 AML 患者的异常炎症，以改善治疗反应和疾病进展。 这一目标将通过两个独立但互补的具体目标来实现。 (1) 利用我们庞大的队列 对 1,600 名 AML 患者进行了分子和临床特征分析，并具有明确的炎症状态， 我们将描述那些炎症程度最高和最低的患者，并比较细胞状态、细胞命运 通过全面的多组学方法在单细胞水平上产生免疫反应。 (2) 我们会追踪 不同治疗期间炎症、免疫调节和相关克隆结构的动态 使用集成方法进行相同的多组学分析，首先对纵向收集的患者进行分析 不同治疗期间具有选定基因型的样本，然后是患者衍生的异种移植模型 相同的患者将接受两种不同的治疗方法，然后进行系列分析，从而允许 用于直接比较和确定观察到的变化的特征。最后，我们将测试 抗炎剂（IL-1抑制剂）降低炎症和预防炎症的有效性- 相关的骨髓重塑和较差的治疗反应。在一起，我们的结果将首次， 提供急需的信息，为针对 AML 患者的异常炎症奠定基础。