The Role of miR-29b in NK cell Development in Acute Myeloid Leukemia

miR-29b 在急性髓系白血病 NK 细胞发育中的作用

• 批准号: 9973154
• 负责人: Bethany Mundy-Bosse
• 金额: $ 18.68万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973154
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Address; Antigen Presentation; Aryl Hydrocarbon Receptor; Automobile Driving; Binding; Biological Models; Cell Maturation; Cell Therapy; Cell physiology; Cells; Clinic; Clinical; Defect; Detection; Development; Disease; Disease Progression; Effectiveness; Effector Cell; Environment; FCGR3B gene; FLT3 gene; Foundations; Goals; Growth; Homeostasis; Human; ITGAM gene; Immune; Immune Evasion; Immune system; Immunologic Surveillance; Immunotherapy; Innate Immune System; Institution; Interferon Type II; Interferons; KLRD1 gene; Knock-in; Knowledge; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentors; MicroRNAs; Modeling; Molecular; Mutation; NCAM1 gene; Natural Immunity; Natural Killer Cells; Pathway interactions; Patient-Focused Outcomes; Patients; Penetrance; Population; Production; Property; Reagent; Receptor Signaling; Regulation; Reporting; Research Proposals; Role; Signal Transduction; Solid; Stem cell transplant; Survival Rate; System; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Translating; Tumor-Derived; Viral; Work; adaptive immune response; anticancer treatment; aryl hydrocarbon receptor ligand; cancer cell; career; curative treatments; cytokine; extracellular vesicles; frontier; immune function; improved; in vivo; innate immune mechanisms; leukemia; man; meetings; mouse model; neoplastic cell; novel; novel therapeutics; overexpression; pathogen; promoter; response; success; targeted treatment; transcription factor; tumor; tumor immunology

PROJECT SUMMARY/ABSTRACT Immune evasion is a major mechanism of acute myeloid leukemia (AML) persistence, and represents a barrier for long-term clinical success. There is a critical need for improved therapies for AML since despite recent therapeutic advances, the 5-year-survival rate is still less than 30% overall. Natural killer (NK) cells represent an encouraging frontier for novel anti-cancer treatments as they have the innate ability to identify, target, and kill cancer cells without prior sensitization. Our previous studies have identified a defect in a specific population of maturing NK cells in both a murine model of AML and in AML patients. This defect appears to be mediated by the overexpression of microRNA (miR)-29b, a potential regulator of TBX21 and EOMES, two key transcription factors important for NK cell development. We believe at least part of this negative regulation is due to soluble tumor-derived signals which drive this overexpression of miR-29b in NK cells. We hypothesize that soluble ligands from leukemic blasts both directly elevate miR-29b through the export of extracellular vesicles, as well as indirectly through the activation of the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor expressed in immature NK cells. We have previously shown that AHR modulates early NK cell development, and preliminary studies indicate AHR may bind to and regulate the miR-29b promoter. This preliminary work led to the following specific aims: 1) To determine the mechanism(s) and impact of NK cell dysregulation of miR-29b in AML. 2) To determine the impact of blocking the aryl hydrocarbon receptor pathway on NK cell function in vivo. These aims are important for both defining how AML is able to evade innate immunity, and identifying potential targets for therapeutic intervention. The studies outlined in this proposal will form a solid foundation from which the PI will begin building a successful independent career in the field of tumor immunology and advancing the knowledge and treatment options of cancer. To achieve these goals, the PI has established an extensive network of collaborators and world-class mentors to guide her through the early stages of her career. Additionally, the PI has outlined numerous meetings, courses and educational enrichment activities supported by her institution to further increase the success and effectiveness of her career. Together, the aforementioned activities with this research proposal will provide the framework for her transition into an independent environment and long-term career goals of translating these discoveries to novel therapeutics to improve patient outcomes.

项目摘要/摘要 免疫逃避是急性髓样白血病（AML）持久性的主要机制，代表障碍 为了长期临床成功。由于最近 治疗性进步，5年生存率的总体总体少于30％。天然杀手（NK）细胞代表 新颖的反癌治疗方面令人鼓舞的边界，因为它们具有识别，靶向和目标 杀死癌细胞而无需事先致敏。我们以前的研究已经确定了特定的缺陷 在AML和AML患者的鼠模型中，成熟的NK细胞群体的群体。这个缺陷似乎是 由microRNA（miR）-29b的过表达介导，-29b​​，tbx21和eomes的潜在调节剂，两个键 转录因子对NK细胞发育很重要。我们认为，这一负面法规的至少一部分是 由于可溶性肿瘤衍生的信号，这些信号驱动了NK细胞中miR-29b的过表达。我们假设 从白血病爆炸中的可溶性配体都直接通过外细胞出口来直接提升miR-29b 囊泡以及通过芳基烃受体（AHR）的激活间接地激活的 在未成熟的NK细胞中表达的转录因子。我们以前已经表明AHR调节早期NK 细胞发育，初步研究表明AHR可能与miR-29b启动子结合并调节。这 初步工作导致以下特定目的：1）确定NK细胞的机制和影响 AML中miR-29b的失调。 2）确定阻断芳基烃受体的影响 体内NK细胞功能的途径。这些目标对于定义AML如何逃避很重要 先天免疫，并确定治疗干预的潜在靶标。其中概述了 提案将构成坚实的基础 肿瘤免疫学领域以及癌症的知识和治疗选择。实现 这些目标，PI建立了广泛的合作者和世界一流的导师网络，以指导她 在她职业生涯的早期阶段。此外，PI概述了许多会议，课程和 她的机构支持的教育丰富活动，以进一步提高成功和有效性 她的职业生涯。共同提到的这项研究建议将为 她过渡到独立环境和长期职业目标，将这些发现转化为 新的治疗疗法以改善患者预后。