Exosomal MicroRNA as a Driver of Immune Evasion in AML

外泌体 MicroRNA 作为 AML 免疫逃避的驱动因素

• 批准号: 8793686
• 负责人: Noah Io Hornick
• 金额: $ 4.81万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793686
• 关键词: 3' Untranslated Regions; Acute Myelocytic Leukemia; Acute leukemia; Address; Adhesions; Adult; Age; Antigens; Apoptosis; Binding; Biological Assay; Blast Cell; Bone Marrow; CXCR4 gene; Cell Communication; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Communication; Data; Dendritic Cells; Dendritic cell activation; Development; Diagnosis; Disease; Disease Progression; Disease remission; Down-Regulation; Early Diagnosis; Environment; Event; Evolution; Exposure to; FLT3 gene; Flow Cytometry; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Health; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Home environment; Homing; Immune; Immune Tolerance; Immune response; Immune system; In Vitro; Incidence; Individual; Interleukin-4; Label; Leukemic Cell; Ligation; Literature; Luciferases; Malignant - descriptor; Malignant Neoplasms; Marrow; Mediating; Mediator of activation protein; Membrane; MicroRNAs; Mixed Lymphocyte Culture Test; Molecular Profiling; Mononuclear; Morbidity - disease rate; Mus; Mutation; Non-Malignant; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Plant Roots; Play; Population; Process; Proteins; RNA; Relapse; Reporter Genes; Residual Tumors; Role; Stem cells; Stimulus; T cell response; Time; Transcript; Vesicle; Work; base; cell type; chemotherapy; cytopenia; design; high risk; improved; in vivo; in vivo Model; interest; leukemia; leukemogenesis; migration; mortality; novel; novel strategies; progenitor; response; trafficking

DESCRIPTION (provided by applicant): Acute Myeloid Leukemia (AML), a heterogeneous group of malignancies of the hematopoietic system, is the most common acute leukemia in adults, with an incidence that is expected to increase as the population ages. Although patients often achieve remission after initial treatment with chemotherapy, relapse remains a significant problem, and the majority of patients eventually succumb to their disease. Several significant aspects of the genesis and progression of AML are related to its interaction with the bone marrow microenvironment: the immune system develops a tolerance for the leukemic cells, and patients lose hematopoietic function over time. As the diagnoses of both the initial leukemia and relapse are made through cytopenias, a better understanding of the events culminating in the development of leukemia both initially and in relapse could potentially allow for earlier detection of disease and new approaches to therapy. Exosomes, small membrane-bound vesicles secreted by many cell types, have recently been demonstrated to carry RNA and protein from cell to cell. This process has recently been shown to occur between AML and cells in its microenvironment, and to contribute to disease progression in other malignancies. Of particular interest is the transfer of certain microRNA shown to regulate both dendritic cell (DC) development and function as well as hematopoietic development and niche adhesion. The work proposed here seeks to delineate the contribution of exosomal communication between AML and its environment to the development of immune tolerance and the erosion of hematopoiesis, two key events in leukemogenesis. In order to achieve this goal, it focuses on exosomal microRNA transfer. It will evaluate the effect this process has on the ability of hematopoietic stem cells to home to and engraft and differentiate in the bone marrow, using in vitro exposure of precursors to exosomes isolated under conditions designed to mimic those encountered in the marrow environment, as well as in vivo modeling using immune-deficient mice. It will further examine the ability of AML-exosomes to suppress the capacity of dendritic cells to develop and initiate an immune response, by evaluating differentiation of mononuclear cells to DC, maturation of DC in response to antigen, and the induction of DC apoptosis in response to exosome exposure.

描述（由申请人提供）：急性髓系白血病（AML）是造血系统的一组异质性恶性肿瘤，是成人中最常见的急性白血病，预计其发病率随着人口老龄化而增加。尽管患者在初次化疗后通常会获得缓解，但复发仍然是一个重大问题，大多数患者最终死于疾病。 AML 发生和进展的几个重要方面与其与骨髓微环境的相互作用有关：免疫系统对白血病细胞产生耐受性，随着时间的推移，患者失去造血功能。由于最初的白血病和复发的诊断都是通过血细胞减少症进行的，因此更好地了解最终导致白血病最初和复发的事件可能有助于更早地发现疾病并制定新的治疗方法。外泌体是许多细胞类型分泌的小膜结合囊泡，最近被证明可以在细胞之间携带 RNA 和蛋白质。最近已证明这一过程发生在 AML 及其微环境中的细胞之间，并有助于其他恶性肿瘤的疾病进展。特别令人感兴趣的是某些 microRNA 的转移，其可调节树突状细胞 (DC) 的发育和功能以及造血发育和生态位粘附。本文提出的工作旨在描述 AML 与其环境之间的外泌体通讯对免疫耐受发展和造血功能侵蚀（白血病发生中的两个关键事件）的贡献。为了实现这一目标，它重点关注外泌体 microRNA 转移。它将评估这一过程对造血干细胞在骨髓中归巢、移植和分化的能力的影响，利用前体体外暴露于在模拟骨髓环境中遇到的条件下分离的外泌体，以及例如使用免疫缺陷小鼠进行体内建模。它将通过评估单核细胞向 DC 的分化、DC 对抗原的反应的成熟以及 DC 细胞凋亡的诱导，进一步检查 AML 外泌体抑制树突状细胞发育和启动免疫反应的能力。外泌体暴露。