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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要免疫逃避是急性髓系白血病 (AML) 持续存在的主要机制，也是一种屏障以获得长期的临床成功。迫切需要改进 AML 的治疗方法，因为尽管最近尽管治疗取得进展，但整体 5 年生存率仍低于 30%。自然杀伤 (NK) 细胞代表新型抗癌疗法是一个令人鼓舞的前沿领域，因为它们具有识别、靶向和治疗的先天能力。无需事先致敏即可杀死癌细胞。我们之前的研究已经发现了特定的缺陷 AML 小鼠模型和 AML 患者中成熟的 NK 细胞群。这个缺陷似乎是由 microRNA (miR)-29b 的过表达介导，microRNA (miR)-29b 是 TBX21 和 EOMES 的潜在调节因子，这两个关键对 NK 细胞发育很重要的转录因子。我们认为这种负面监管至少有一部分是这是由于可溶性肿瘤衍生信号驱动 NK 细胞中 miR-29b 的过度表达。我们假设来自白血病原始细胞的可溶性配体都通过细胞外的输出直接升高 miR-29b 囊泡，以及间接通过芳基碳氢化合物受体（AHR）的激活，一种配体激活未成熟 NK 细胞中表达的转录因子。我们之前已经证明 AHR 调节早期 NK 细胞发育，初步研究表明 AHR 可能结合并调节 miR-29b 启动子。这前期工作实现了以下具体目标：1）确定 NK 细胞的机制和影响 AML 中 miR-29b 的失调。 2) 确定阻断芳烃受体的影响体内 NK 细胞功能的通路。这些目标对于定义反洗钱如何能够规避都很重要先天免疫，并确定治疗干预的潜在目标。本文概述的研究提案将为 PI 开始在以下领域建立成功的独立职业生涯奠定坚实的基础：肿瘤免疫学领域并推进癌症的知识和治疗选择。达到为了实现这些目标，PI 建立了广泛的合作者网络和世界级导师来指导她在她职业生涯的早期阶段。此外，PI 还概述了许多会议、课程和她所在机构支持的教育丰富活动，以进一步提高成功率和有效性她的职业生涯。上述活动与本研究计划一起将为她向独立环境的转变以及将这些发现转化为长期职业目标改善患者治疗效果的新疗法。