SUMMARY The last decade has seen an unparalleled pace of cancer-focused discovery enabled by disruptive technologies. However, for many malignancies, such as acute myeloid leukemia (AML), survival of the disease remains unchanged despite a more granular description of its genomic landscape. My research program seeks to apply new approaches in functional genomics and chemical biology to validate and translate emerging cancer dependencies in AML and other malignancies defined by simple genomes, particularly pediatric cancers. In this proposal, I build upon our past success in 1) inventing new approaches to small-molecule discovery 2) applying state-of-the-art chemical and functional genomic screens to identify new therapeutic targets in leukemia, Ewing sarcoma, and neuroblastoma, and in 3) translating our discoveries to clinical trials for patients suffering from these diseases. Primarily focusing on AML, my future research program seeks to 1) deploy genetic approaches to validate candidate cancer dependencies, 2) discover and test new small- molecule inhibitors of cancer dependencies, and 3) dissect the mechanisms of each target and its role in AML. I will begin with the study of targets that have emerged in our research as relevant in high-risk AML subtypes: the cytoplasmic kinase spleen tyrosine kinase (SYK); a serine-threonine kinase glycogen synthase kinase 3 alpha (GSK-3?), a mitochondrial enzyme involved in folate metabolism, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2); and a member of the cohesin complex: stromal antigen 2 (STAG2). In some cases, such as Ewing sarcoma and STAG2, I will extend testing to other disease contexts where the target is relevant and my laboratory has expertise. With deep expertise in the molecular pathogenesis and care of patients with AML; experience leading highly multi-disciplinary teams focused on high-throughput screening for this disease and a rich network of chemistry, biology, and clinical collaborators, I am uniquely positioned to succeed in the 7 year research plan delineated in this proposal.