Defining and targeting the metabolic landscape in Acute Myeloid Leukemia

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PROJECT SUMMARY/ABSTRACT Acute Myeloid Leukemia (AML) is an aggressive blood cancer that arises from the aberrant expansion of mutated myeloid-skewed hematopoietic stem and progenitor cells (HSPCs). Given that the current 5-year survival rate for AML patients is below 25%, novel, more effective therapies are desperately needed. Targeting cellular energy production has recently become as a promising point of therapeutic intervention in many cancers including AML. This study aims to uncover the metabolic alterations that support AML pathogenesis and to exploit this information to identify new potential therapeutic targets in AML. We have found that compared to healthy HSPCs, AML cells are more sensitive to perturbations in mitochondria, which are the epicenters of cellular energy. In search of molecular pathways that selectively support metabolism in AML cells but not healthy HSPCs, we recently discovered that the kinase PKCε supports AML survival and progression by preserving redox balance. To gain a deeper understanding of how PKCε does this, we carried out a proteomics analysis and found that PKCε regulates the expression of several mitochondrial and metabolic proteins, including Electron Transport Chain (ETC) complex subunits, transporters, and metabolic enzymes. Follow-up metabolomics analyses in AML cells confirmed that several metabolic pathways, in particular glycolysis and gluconeogenesis, are severely disrupted by PKCε inhibition. A comparative analysis of proteomic and metabolomic data revealed that PKCε regulates multiple enzymatic pinch points within glycolysis. To identify which of the PKCε-regulated glycolytic enzymes may be supporting AML, we performed a retrospective analysis of AML patient gene expression data and observed that increased expression of Enolase (ENO1) is associated with significantly worse AML patient outcomes. Additionally, we found that inhibition of ENO1 activity either genetically or chemically significantly reduces the growth and survival of AML but, of critical importance, not healthy HSPCs. The aims of this proposal are to leverage these observations by: 1) Defining the role of PKCε in AML cellular metabolism; 2) Assessing the therapeutic potential of targeting PKCε-regulated metabolic enzymes, such as ENO1, in AML. The results of this proposal will uncover new metabolic dependences in AML as well as molecular targets that can serve as a basis for developing novel AML therapies. Based on these preliminary data and proposed studies, the central mission of my career plan is to decipher how metabolism influence leukemogenesis and to identify new molecular targets that can be exploited for therapeutic intervention.