The roles of AP-1 pathway activation in NK cell development and exhaustion programming in AML

AP-1 通路激活在 NK 细胞发育和 AML 衰竭编程中的作用

• 批准号: 10751755
• 负责人: Erin G. Jeremy
• 金额: $ 4.2万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751755
• 关键词: Acute Myelocytic Leukemia; Adult; Automobile Driving; Blood Cells; Cell Line; Cell Maturation; Cell Separation; Cell physiology; Cells; Chromatin; Clinical; Cre lox recombination system; DNA Methylation; Data; Defect; Development; Diagnosis; Epigenetic Process; FOS Protein; Family; Gene Expression Profiling; Genetic Transcription; Hematologic Neoplasms; Homeostasis; Human; Immune; Immune Evasion; Immunologic Surveillance; Immunotherapeutic agent; Impairment; In Vitro; Interferon Type II; Lymphoid Cell; MAPK8 gene; MEK inhibition; MEKs; Mediating; Mus; Myelogenous; Natural Killer Cells; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Post-Translational Protein Processing; Precursor Natural Killer Cell; Production; Proteins; Regulation; Role; Series; Signal Pathway; Signal Transduction; Survival Rate; Testing; Therapeutic; Transcriptional Activation; Treatment Efficacy; Work; Xenograft Model; activating transcription factor; acute myeloid leukemia cell; cancer cell; checkpoint receptors; design; dimer; epigenetic profiling; exhaustion; functional disability; immune checkpoint; in vivo; in vivo Model; inhibitor; leukemia; leukemia relapse; mouse model; novel; p38 Mitogen Activated Protein Kinase; pharmacologic; preservation; prevent; programs; small molecular inhibitor; stem cells; targeted treatment; therapeutic target; therapeutically effective; transcription factor; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT The 5-year overall survival rate for acute myeloid leukemia (AML) is less than 35%, making it the most fatal leukemia in adults. Natural killer (NK) cells are a type of innate lymphoid cell (ILC) capable of recognizing and killing malignant cells. We have previously demonstrated that NK cells are developmentally and functionally impaired in AML. These impairments correlate to worse overall survival and clinical outcomes, highlighting the importance of understanding the mechanisms by which AML alters NK cell development and function. To better understand these defects, we assessed the transcriptional and epigenetic landscape of NK cells in AML and discovered that mature NK cells from AML patients are globally hypomethylated when compared to normal controls and have abnormal activation of activating protein-1 (AP-1). AP-1, which is a set of transcription factor (TF) dimers primarily composed of Jun and Fos family proteins, has been shown to regulate ILC development and homeostasis, chromatin accessibility, and immune cell exhaustion. The activity of AP-1 is regulated by upstream mitogen activated protein kinases p38, JNK and ERK through transcription activation and post- translational modifications. In this proposal, we will determine how the MEK/ERK signaling branch of the AP-1 signaling pathway contributes to NK cell defects in AML and whether development and function can be restored through AP-1 pathway inhibition. We hypothesize that AP-1 signaling is a critical regulator of NK cell development and function that becomes dysregulated in AML. These studies will first describe the mechanism(s) by which the AP-1 pathway influences NK cell development in the setting of AML (Aim 1). We will use pharmacologic agents as well as CRISPRcas9 editing to understand how aberrant AP-1 signaling skews human NK cell development. We will also determine the functional consequences of aberrant AP-1 activation in mature NK cells (Aim 2). Finally, we will assess the therapeutic efficacy of AP-1 pathway regulation in multiple in vivo models of AML (Aim 3). Results from these studies will further our mechanistic understanding of NK cell development in AML to better inform therapeutic strategies.

项目总结/摘要 急性髓细胞白血病（AML）的5年总生存率低于35%，使其成为最致命的白血病 成人白血病自然杀伤（NK）细胞是一种能够识别和杀伤肿瘤细胞的先天性淋巴样细胞（ILC）。 杀死恶性细胞我们以前已经证明，NK细胞在发育和功能上是 在AML中受损。这些损伤与较差的总生存率和临床结局相关，突出了 了解AML改变NK细胞发育和功能的机制的重要性。更好地 了解这些缺陷后，我们评估了AML中NK细胞的转录和表观遗传格局， 发现与正常人相比，AML患者的成熟NK细胞总体上是低甲基化的 控制并具有激活蛋白-1（AP-1）的异常激活。AP-1是一组转录因子， (TF)主要由Jun和Fos家族蛋白组成的二聚体已被证明可调节ILC的发育 和稳态、染色质可及性和免疫细胞耗竭。AP-1的活性受以下因素的调节： 上游有丝分裂原激活蛋白激酶p38、JNK和ERK通过转录激活和后 翻译修饰在这个提议中，我们将确定AP-1的MEK/ERK信号传导分支是如何被激活的。 信号通路有助于AML中的NK细胞缺陷以及发育和功能是否可以恢复 通过AP-1通路抑制。我们假设AP-1信号是NK细胞发育的关键调节因子 在AML中变得失调。这些研究将首先描述 AP-1通路影响AML背景下的NK细胞发育（目的1）。我们将使用药物 以及CRISPRcas 9编辑，以了解异常AP-1信号传导如何扭曲人类NK细胞发育。 我们还将确定成熟NK细胞中异常AP-1激活的功能后果（目的2）。 最后，我们将评估AP-1通路调节在AML的多种体内模型中的治疗功效（Aim 3）。这些研究的结果将进一步加深我们对AML中NK细胞发育机制的理解， 提供治疗策略。