Manipulating mitobiogenesis by targeting ME2

Acute myeloid leukemia (AML) remains a highly lethal cancer and is increasing in incidence. Targeted therapies are modestly improving patient outcomes but only in small subsets of patients. We focused on the long-noted features of AML of increased mitochondrial number and increased oxidative phosphorylation dependence across genotypes to discover a distinct vulnerability to malic enzyme2 (ME2). We demonstrated that ME2 connects TCA activity with mitobiogenesis by serving as a fumarate sensor and regulating mitochondrial gene translation: mitochondrial genes encode proteins of the electron transport pathway. When ME2 is inhibited, metabolic crisis ensues and AML cells undergo apoptosis. This is due to the fumarate binding and not the catalytic activity of ME2. Animals bearing human AML cells have markedly improved survival with ME2-fumarate binding inhibition. Notably, normal human and mouse hematopoietic cells express lower levels of ME2 and normal mouse hematopoietic cells were unaffected by ME2 inhibition in vivo. We have encouraging early data for primary and secondary screening assays for ME2 inhibition based on the dimerization of ME2 induced by fumarate affecting its catalytic activity. We seek to optimize and apply these assays in a high throughput manner to define small molecule inhibitors of ME2 dimerization with the goal of advancing genotype agnostic therapy for AML.