Project Summary Genetic and functional data have demonstrated the importance of somatic mutations in signaling effectors and in epigenetic modifiers in the pathogenesis of myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). However, the mechanisms by which these two classes of leukemia disease alleles cooperate to induce transformation, and how coordinate mutations in signaling pathways and in epigenetic regulators affect the response to targeted therapy, has not been fully elucidated. Here we propose to investigate how mutations in signaling effectors cooperate with mutations in epigenetic regulators to induce myeloid transformation, and how these mutations influence the response to targeted therapies including the development of therapeutic resistance. We will then extend our studies to investigate whether combination therapeutic approaches can achieve increased efficacy in models of myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). The long-term goals of this proposal are to characterize novel mechanisms by which oncogenic disease alleles cooperate to induce leukemogenesis, and to credential novel combination strategies that can be investigated in the clinical context. We will investigate this using a combination of novel, genetically accurate animal models, epigenomic studies in murine models and patient samples, and preclinical therapeutic studies aimed at rational design of combination therapeutic strategies. Our studies have a mechanistic focus, but are aimed to rapidly translate these insights to the clinical context.