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

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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.