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.

项目概要/摘要 急性髓系白血病（AML）的 5 年总生存率低于 35%，是最致命的疾病 成人白血病。自然杀伤 (NK) 细胞是一种先天性淋巴细胞 (ILC)，能够识别和 杀死恶性细胞。我们之前已经证明 NK 细胞在发育和功能上 AML 受损。这些损害与较差的总体生存率和临床结果相关，凸显了 了解 AML 改变 NK 细胞发育和功能的机制的重要性。为了更好 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景观， 发现与正常人相比，来自 AML 患者的成熟 NK 细胞整体甲基化程度较低 控制并异常激活激活蛋白 1 (AP-1)。 AP-1，一组转录因子 (TF) 二聚体主要由 Jun 和 Fos 家族蛋白组成，已被证明可以调节 ILC 发育 以及稳态、染色质可及性和免疫细胞耗竭。 AP-1 的活性受以下因素调节 通过转录激活和后转录激活上游有丝分裂原激活蛋白激酶 p38、JNK 和 ERK 翻译修饰。在本提案中，我们将确定 AP-1 的 MEK/ERK 信令分支如何 信号通路导致AML中NK细胞缺陷以及能否恢复发育和功能 通过AP-1途径抑制。我们假设 AP-1 信号传导是 NK 细胞发育的关键调节因子 以及在 AML 中变得失调的功能。这些研究将首先描述 AP-1 通路影响 AML 中 NK 细胞的发育（目标 1）。我们将使用药物制剂 以及 CRISPRcas9 编辑，以了解异常的 AP-1 信号传导如何影响人类 NK 细胞的发育。 我们还将确定成熟 NK 细胞中异常 AP-1 激活的功能后果（目标 2）。 最后，我们将评估 AP-1 通路调节在多种 AML 体内模型中的治疗效果（目的 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，以便更好地了解 AML 中 NK 细胞发育的机制。 告知治疗策略。