Acute myelogenous leukemia (AML) is the most common acute leukemia. It occurs in all age groups and produces considerable morbidity and mortality. Advances in treating AML are much less than experienced in other hematologic malignancies. Therefore, we are in desperate need of novel therapeutic approaches for AML. This proposal initiates investigation into a completely novel targeted therapeutic approach for AML, based on our recent discovery that the cancer-related M2 isoform of the ATP-producing enzyme pyruvate kinase (PKM2) interacts with the inositol 1,4,5-trisphosphate receptor (InsP3R), an InsP3-gated Ca2+ channel located on the endoplasmic reticulum (ER). Our theory is that this interaction generates compartmentalized glycolytic ATP synthesis that supports ER Ca2+ uptake via ER-associated Ca2+-ATPase pumps and regulates InsP3R-mediated Ca2+ release from the ER. To test this theory we developed a peptide inhibitor of PKM2-InsP3R interaction, which we refer to as PKM2- DP (PKM2-Displacing Peptide). We find that treating AML cell lines and primary AML cells from patient samples with TAT-PKM2-DP causes high amplitude sustained Ca2+ elevation, inducing cell death. This observation indicates that PKM2-InsP3R interaction supports AML cell survival, suggesting that PKM2- InsP3R interaction may be an effective target for AML treatment. Therefore, this proposal will further elucidate the pro-survival function of PKM2-InsP3R interaction and initiate pre-clinical studies using an orthotopic mouse model of human AML to test the therapeutic efficacy of targeting PKM2-InsP3R interaction for AML treatment. In sum, research outlined in this proposal will both generate novel insight into the role of PKM2 in cancer and lead to development of a new therapeutic approach for AML that may also extend to other malignancies.