The role of inflammation in the regulation of immune response in acute myeloid leukemia
The role of inflammation in the regulation of immune response in acute myeloid leukemia
批准号:
10729281
负责人:
Iannis Aifantis
金额:
$57.03万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-06 至 2028-06-30
关键词:
ATAC-seqAcute Myelocytic LeukemiaAcute leukemiaAdultAnimal ModelAnti-Inflammatory AgentsAntibodiesAtlasesB-LymphocytesB-cell receptor repertoire sequencingBlast CellBone MarrowBone remodelingCellsCellular Indexing of Transcriptomes and Epitopes by SequencingCensusesChromatinClinicalClonalityCollectionCoupledCytarabineDataDaunorubicinDevelopmentDiseaseDisease ProgressionEpitopesEventExhibitsGene ExpressionGenerationsGenesGeneticGenomicsGenotypeGoalsHematopoietic stem cellsHumanIL1R1 geneIRAK1 geneImmuneImmune responseImmune systemImmunocompetentInferiorInflammationInflammation MediatorsInflammatoryInflammatory ResponseInterleukin-1Leukemic CellMalignant - descriptorMalignant NeoplasmsMediatingMediatorMembrane ProteinsModelingMolecularMusMutateMutationMyeloid CellsMyeloproliferative diseaseOther GeneticsOutcomePatientsPhenotypePlayPopulationPredispositionRegimenResolutionRiskRoleSamplingSignal TransductionSpecificityStructureSubgroupSupporting CellT-LymphocyteTestingTherapeuticTimeTissuesTreatment Protocolscancer cellcell transformationcohortdesigneffectiveness testingexome sequencingimmunoregulationimprovedindexinginhibitorinsightleukemialeukemogenesismonocytemouse modelmultiple omicsnegative affectnew therapeutic targetnovelpreventprotein expressionresponsesingle cell technologysingle-cell RNA sequencingstandard of caresurvival outcometargeted agenttranscriptometranscriptome sequencingtreatment effecttreatment responsetumortumor microenvironmenttumor progressiontumor-immune system interactions
中文摘要
项目总结/文摘
英文摘要
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.
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专著(0)
科研奖励(0)
会议论文
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依托单位:
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Post-translational control of cancer cell stress response and metastasis
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Long non-coding RNAs in hematopoiesis and blood malignancy
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依托单位:
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依托单位:
海外基金