Project Summary/Abstract Treatment options that effectively cure patients diagnosed with acute myeloid leukemia (AML) continue to represent an area of unmet need in oncology clinical care. While remission rates in AML patients can reach upwards of 80% under the current frontline therapy paradigm, nearly all patients relapse with treatment refractory disease less than 5 years after diagnosis. Relapse driven by therapy resistant cells that persist in the body after treatment (defined as minimal residual disease) is the principal source of fatality in AML patients. Therefore, understanding how and where these leukemic cells survive treatment in vivo may help advance the rational development of highly synergistic combination therapies for the treatment of AML. Using a functional genomic approach (in vivo RNAi) and a new mouse model of AML chemoresistance (ChemoR) generated in our labs, we have identified several putative mediators of therapy resistance. Transcriptional profiling of the ChemoR model allowed us to generate a chemoresistance gene signature that we overlapped with the results of the shRNA screen to identify high-confidence genes of interest. The top genes from a ranked list of the most highly overexpressed genes in ChemoR cells and the top depleted genes from the shRNA screen in the context of therapy treatment were selected as high interest hits and subsequently tagged for individual follow-up experiments. One of the most highly rated genes on that list encodes the Liver Kinase B1 (Lkb1) activator Stradα (STE20-related kinase adaptor alpha), suggesting that this gene may represent an uncharacterized therapeutic target that promotes AML resistance. The goals of this project are to investigate what role Stradα plays in human AML chemoresistance and to dissect the putative resistance mechanism mediated by this gene. To address this question I propose to: 1. Address the role of STRADα in human AML response to frontline chemotherapy. 2. Characterize the basic drug resistance mechanism mediated by Stradα in AML. By addressing these aims, I can gain insight into whether increased signaling through STRADα represents a novel genetic liability of AMLs in the context of frontline therapy that can be exploited to better treat this disease. Work on this project will also foster my development as an independent physician-scientist by placing me at the interface between clinical and basic science investigators. Since a critical component of this work is to determine whether STRADα is biologically relevant in human AML chemoresistance, I will learn how to translate basic science observations generated from hypothesis driven experiments into potential therapeutic strategies that could be applied clinically to potentiate the effects of frontline agents. Ultimately, working on this project will train me in the overall approach for addressing key translational questions I will focus on later in my career.