Metabolic analysis of leukemia leads to the development of novel therapies

Abstract

Cancer cells utilize different metabolic characteristics of normal cells to promote their growth with the production of energy and the synthesis of nucleic acids, amino acids, and lipids. Contrary to previous understanding that cancer cells uniformly prefer to utilize aerobic glycolysis, advances in analysis technology such as comprehensive metabolomic analysis and metabolic flux analysis have revealed that different cancer types, genetic mutations, and even cancer stem cells have different metabolic characteristics. The energy production mechanisms of leukemic cells for survival and proliferation are also being elucidated. Although the glycolytic system is essential for leukemogenesis, LSC survival reportedly depends on ATP production of OXPHOS in mitochondria, and chemotherapy resistance is correlated with OXPHOS activity. We are analyzing the energy metabolism of refractory leukemia with an extracellular flux analyzer and identifying novel therapeutic targets with the combination of metabolome and transcriptome analyses. The main mechanism of the combination of venetoclax and azacitidine is to suppress OXPHOS by decreasing glutathione levels in LSCs and inhibiting amino acid metabolism, and AML metabolism analysis can identify drug sensitivity and synergistic combination drugs. In the future, the integration of metabolic analysis with further analysis techniques such as single-cell metabolomics and lipidome analysis is promising for the development of novel therapeutic agents targeting leukemia energy metabolism.