Mechanistic characterization of the dependency of Acute Myeloid Leukemia cells on the metabolic enzyme lactate dehydrogenase A

Details

Supervisors

van Gastel, Nick

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Acute myeloid leukemia (AML) is a disease affecting the hematopoietic system, caused by the abnormal accumulation of undifferentiated hematopoietic myeloid progenitor cells in the bone marrow microenvironment. AML is a complex disorder characterized by its heterogeneity. This heterogeneity arises from acquisition of multiple genetic alterations within AML cells. AML cells also possess a highly active metabolism and an adaptive capacity to switch their metabolic networks, enabling their survival. Recent studies have highlighted that metabolic properties of AML cells are linked to relapse in patients. This master thesis aims to understand metabolic programs employed by AML cells. By understanding the intricate mechanisms of metabolism in these cells, we aim to uncover new insights that can generate potential therapeutic strategies. To evaluate metabolic dependencies of AML cells, we used over 20 metabolic inhibitors targeting distinct branches of central metabolic activities. Our metabolic inhibitor screen revealed metabolic vulnerabilities, of which LDHA enzyme inhibition by FX11 was one of the strongest. Our hypothesis suggests that leukemic cells rely on the LDHA, converting pyruvate into lactate, for survival, and when LDHA is inhibited, AML cells display significantly increased apoptosis. We assessed the metabolic changes by measuring glycolytic and OXPHOS activity, levels of reactive oxygen species and levels of intracellular metabolites in AML cells after FX11 treatment. Our results show that LDHA inhibition reduces glycolytic activity, TCA cycle activity and increases ROS levels, but that this increased ROS level is not responsible for the observed AML cell death. Instead, we found that LDHA is essential to maintain NAD+/NADH ratio in AML cells. Our future perspectives are to enhance the impact of our findings by deeper investigating metabolic outcomes after LDHA inhibition and the synergistic effects of FX11 when combined with other existing anti-leukemic drugs with the goal of improving therapeutic efficacy. Additionally, our findings will be validated using patient samples and in vivo using a mouse model of AML as a prerequisite for further investigations in clinical trials.