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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘