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

项目摘要/摘要 免疫逃逸是急性髓系白血病(AML)持续存在的主要机制，是一种障碍 以取得长期的临床成功。急切需要改进AML的治疗方法，因为尽管最近 尽管治疗取得了进展，但总体而言，5年存活率仍不到30%。自然杀伤(NK)细胞代表 新的抗癌治疗是一个令人鼓舞的前沿领域，因为它们具有天生的识别、靶向和 无需事先致敏即可杀死癌细胞。我们之前的研究发现了一个特定的缺陷 AML小鼠模型和AML患者中成熟NK细胞的数量。这一缺陷似乎是 Tbx21和eome的潜在调节因子microRNA(MiR)-29b的过度表达 转录因子对NK细胞发育很重要。我们认为，这种负面监管至少有一部分是 这是由于可溶的肿瘤信号驱动了NK细胞中miR-29b的过度表达。我们假设 白血病细胞的可溶性配体通过胞外输出直接上调miR-29b 囊泡，以及通过激活芳香烃受体(AHR)间接地激活，AHR是一种激活的配体 转录因子在未成熟的NK细胞中表达。我们之前已经证明AHR对早期NK细胞有调节作用 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 初步工作的具体目标如下：1)确定NK细胞的作用机制(S)及其影响 急性髓系白血病miR-29b基因表达异常。2)确定阻断芳烃受体的影响 体内NK细胞功能的途径。这些目标对于定义AML如何能够规避都很重要 先天免疫，并确定潜在的治疗干预目标。这篇文章中概述的研究 提案将为PI开始成功的独立职业生涯奠定坚实的基础 在肿瘤免疫学领域，推进癌症的知识和治疗选择。要实现 为了实现这些目标，PI建立了广泛的合作者网络和世界级的导师来指导她 在她职业生涯的早期阶段。此外，国际刑警组织还概述了许多会议、课程和 由她的机构支持的教育丰富活动，以进一步提高成功和成效 她职业生涯的一部分。上述活动与本研究提案一起，将提供以下框架 她向独立环境的过渡和将这些发现转化为 改善患者预后的新疗法。

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.