AML Metabolism: A Dynamic Continuum of Functional Dependencies

Metabolic reprogramming is increasingly recognized as a fundamental component of acute myeloid leukemia (AML) biology, but AML cannot be defined by a single metabolic phenotype. Leukemic cells occupy dynamic metabolic states shaped by differentiation, genetic background, the bone marrow microenvironment, and therapeutic pressure. In this Review, we propose that metabolic biomarkers should capture functional dependencies and metabolic plasticity rather than static metabolic states, with functional dependencies defined as the reliance of AML cells on a specific metabolic pathway or process for their survival, proliferation or maintenance, rather than a simple glycolytic-versus-oxidative dichotomy. Normal hematopoietic stem cells (HSCs), leukemic stem cells (LSCs), and bulk AML blasts display distinct metabolic programs. Quiescent HSCs maintain a low-energy state, whereas LSCs rely strongly on mitochondrial oxidative phosphorylation (OXPHOS), amino acid metabolism, mitochondrial quality control, and antioxidant defenses. AML blasts exhibit greater metabolic heterogeneity and can switch between glycolytic and oxidative pathways. Importantly, increased mitochondrial activity does not necessarily indicate an LSC phenotype, as therapy-resistant AML cells may acquire enhanced OXPHOS, fatty acid oxidation (FAO), and mitochondrial fitness as adaptive states. Acute promyelocytic leukemia (APL) provides a model of lineage-specific metabolic rewiring, with PML::RARA suppressing glycolysis while promoting FAO, TCA cycle activity, OXPHOS, and arginine-associated anaplerosis. We propose that metabolic biomarkers should identify functional dependencies and escape routes. Integrating metabolic profiling with multi-omics approaches may enable identification of AML subgroups with distinct vulnerabilities and guide rational combination therapies.