Metabolic Reprogramming of Leukemia Stem Cells as a Novel Therapeutic Target for Relapsed Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) remains a devastating hematologic malignancy with particularly poor outcomes in relapsed and refractory disease, where five-year overall survival approximates 10%. Leukemia stem cells (LSCs), a quiescent subpopulation with self-renewal capacity, represent the primary drivers of disease persistence, therapeutic resistance, and relapse. This review comprehensively examines the metabolic reprogramming that distinguishes LSCs from both normal hematopoietic stem cells and bulk AML blasts, with emphasis on bioenergetic adaptations acquired during therapy resistance. Primitive CD34⁺CD38⁻ LSCs demonstrate dependency on mitochondrial oxidative phosphorylation (OXPHOS) fueled by amino acid and fatty acid catabolism, maintaining low reactive oxygen species levels through specialized quality control mechanisms. Critically, relapsed LSCs exhibit enhanced metabolic plasticity, shifting reliance toward nicotinamide adenine dinucleotide (NAD⁺) salvage via nicotinamide phosphoribosyltransferase (NAMPT) upregulation, alongside increased fatty acid oxidation and one-carbon metabolism. The bone marrow microenvironment contributes to metabolic resistance through mitochondrial transfer from mesenchymal stromal cells and systemic nutrient modulation. Therapeutic targeting of these vulnerabilities has yielded promising agents including NAMPT inhibitors (KPT-9274), glutaminase-1 inhibitors (telaglenastat), and electron transport chain inhibitors (IACS-010759), currently under clinical evaluation. However, metabolic plasticity and clonal heterogeneity necessitate combinatorial approaches and biomarker-guided patient selection. This review highlights that understanding LSC-specific metabolic dependencies offers unprecedented opportunities to eliminate therapy-resistant populations, though successful clinical translation requires overcoming challenges of metabolic redundancy, defining therapeutic windows that spare normal hematopoiesis, and implementing dynamic monitoring strategies to track bioenergetic evolution during disease progression.