The differential activation of metabolic pathways in leukemic cells depending on their genotype and micro-environmental stress.

ABSTRACT

INTRODUCTION: Acute myeloid leukemia (AML) is characterized by a set of malignant proliferations leading to an accumulation of blasts in the bone marrow and blood. The prognosis is pejorative due to the molecular complexity and pathways implicated in leukemogenesis. OBJECTIVES: Our research was focused on comparing the metabolic profiles of leukemic cells in basal culture and deprivation conditions to investigate their behaviors under metabolic stress. METHODS: We performed untargeted metabolomics using 1H HRMAS-NMR. Five human leukemic cell lines-KG1, K562, HEL, HL60 and OCIAML3-were studied in the basal and nutrient deprivation states. A multivariate analysis of the metabolic profile was performed to find over- or under- expressed metabolites in the different cell lines, depending on the experimental conditions. RESULTS: In the basal state, each leukemic cell line exhibited a specific metabolic signature related to the diversity of AML subtypes represented and their phenotypes. When cultured in a serum-free medium, they showed quick metabolic adaptation and continued to proliferate and survive despite the lack of nutrients. Low apoptosis was observed. Increased phosphocholine and glutathione was a common feature of all the observed cell lines, with the maximum increase in these metabolites at 24 h of culture, suggesting the involvement of lipid metabolism and oxidative stress regulators in the survival mechanism developed by the leukemic cells. CONCLUSIONS: Our study provides new insights into the metabolic mechanisms in leukemogenesis and suggests a hierarchy of metabolic pathways activated within leukemic cells, some dependent on their genotypes and others conserved among the subtypes but commonly induced under micro-environmental stress.