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

项目总结/摘要 免疫逃避是急性髓系白血病（AML）持续存在的主要机制， 长期的临床成功。迫切需要改进AML的疗法，因为尽管最近 尽管治疗取得了进展，但总体5年生存率仍低于30%。自然杀伤（NK）细胞代表 这是一个令人鼓舞的新的抗癌治疗前沿，因为它们具有识别、靶向和治疗癌症的先天能力。 杀死癌细胞而无需预先致敏。我们以前的研究已经确定了一个特定的缺陷， 在AML的鼠模型和AML患者两者中的成熟NK细胞群体。这一缺陷似乎是 由microRNA（miR）-29b的过表达介导，这是TBX 21和EOMES的潜在调节因子， 对NK细胞发育重要的转录因子。我们认为，至少部分负面监管是 这是由于可溶性肿瘤来源的信号驱动NK细胞中miR-29 b的这种过表达。我们假设 来自白血病母细胞的可溶性配体都通过细胞外基质的输出直接升高miR-29 b， 囊泡，以及间接通过激活芳香烃受体（AHR），配体激活 在未成熟NK细胞中表达的转录因子。我们以前已经证明，AHR调节早期NK细胞， 细胞发育，初步研究表明AHR可能结合并调节miR-29 b启动子。这 初步工作导致了以下具体目标：1）确定NK细胞的机制和影响 AML中miR-29 b的失调。2)确定阻断芳香烃受体的影响 NK细胞在体内的功能。这些目标对于确定反洗钱如何能够逃避 先天免疫，并确定潜在的治疗干预的目标。本文中概述的研究 提案将形成一个坚实的基础，PI将开始建立一个成功的独立职业生涯， 肿瘤免疫学领域和推进癌症的知识和治疗选择。实现 为了实现这些目标，PI建立了广泛的合作者和世界级导师网络， 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充实活动，以进一步提高成功率和有效性 她的职业生涯。上述活动和本研究提案将共同为以下方面提供框架： 她过渡到一个独立的环境和长期的职业目标，将这些发现， 新的治疗方法，以改善患者的结果。

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.