Metabolic stress adaptation, redox homeostasis, and autophagy in leukemic stem cell persistence in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is driven by the constitutive tyrosine kinase activity of the BCR::ABL1 fusion protein and is effectively treated with tyrosine kinase inhibitors (TKIs). However, therapeutic resistance and the persistence of leukemic stem cells (LSCs) remain important clinical challenges. TKI resistance cannot be explained solely by BCR::ABL1-dependent mechanisms and involves a complex interplay between signaling, metabolic, redox, and autophagic adaptations. In this review, we integrate current knowledge on BCR::ABL1-dependent and BCR::ABL1-independent resistance mechanisms, with particular emphasis on metabolic reprogramming in CML LSCs and TKI-resistant leukemic cells. Available evidence indicates that primitive CML populations can exhibit enhanced mitochondrial oxidative metabolism, whereas TKI-resistant and persistent leukemic populations may engage glycolysis, the pentose phosphate pathway, fatty acid oxidation, and amino acid metabolism to different extents. Rather than representing mutually exclusive metabolic states, oxidative and glycolytic programs may coexist and vary according to cellular differentiation, microenvironmental conditions, and therapeutic pressure. These metabolic adaptations are interconnected with major signaling pathways, including PI3K/AKT/mTOR, JAK/STAT, Wnt/β-catenin, and Hedgehog signaling, as well as with redox regulation and autophagy. Preclinical studies suggest that combining TKIs with metabolism- or autophagy-directed interventions may help exploit vulnerabilities associated with leukemic persistence. However, the heterogeneity of metabolic phenotypes, potential toxicity to normal hematopoietic cells, and limited clinical validation of candidate metabolic biomarkers currently constrain their therapeutic translation. Further studies are therefore required to determine which metabolic dependencies are clinically actionable and whether biomarker-guided strategies can improve the targeting of persistent CML cells.