The metabolic reprogramming in acute myeloid leukemia patients depends on their genotype and is a prognostic marker

Abstract

Abstract Leukemic cells display some alterations in metabolic pathways, which play a role in leukemogenesis and in patients’ prognosis. To evaluate the characteristics and the impact of this metabolic reprogramming, we explore the bone marrow samples from 54 de novo acute myeloid leukemia (AML) patients, using an untargeted metabolomics approach based on proton high-resolution magic angle spinning-nuclear magnetic resonance. The spectra obtained were subjected to multivariate statistical analysis to find specific metabolome alterations and biomarkers correlated to clinical features. We found that patients display a large diversity of metabolic profiles, according to the different AML cytologic subtypes and molecular statuses. The link between metabolism and molecular status was particularly strong for the oncometabolite 2-hydroxyglutarate (2-HG), whose intracellular production is directly linked to the presence of isocitrate dehydrogenase mutations. Moreover, patients’ prognosis was strongly impacted by several metabolites, such as 2-HG that appeared as a good prognostic biomarker in our cohort. Conversely, deregulations in phospholipid metabolism had a negative impact on prognosis through 2 main metabolites (phosphocholine and phosphoethanolamine), which could be potential aggressiveness biomarkers. Finally, we highlighted an overexpression of glutathione and alanine in chemoresistant patients. Overall, our results demonstrate that different metabolic pathways could be activated in leukemic cells according to their phenotype and maturation levels. This confirms that metabolic reprogramming strongly influences prognosis of patients and underscores a particular role of certain metabolites and associated pathways in AML prognosis, suggesting common mechanisms developed by leukemic cells to maintain their aggressiveness even after well-conducted induction chemotherapy.