Oxidative Phosphorylation and Fatty Acid Oxidation Are Central to Mitochondrial Metabolism Rewiring in CML Stem/Progenitor Cell Survival

Background/Objectives: Quiescent leukemia stem cells (LSCs) are self-renewing, pluripotent cells that present a major obstacle to the successful curative treatment of chronic myeloid leukemia (CML). LSCs function independently of BCR::ABL1 signaling and persist following tyrosine kinase inhibitor treatment. The mechanisms enabling LSC survival are a central focus of current CML research. This review details the complex relationship between signaling pathways and discusses recent advancements in energy metabolism research within the pathogenesis of CML. Discussion: Energy metabolism is critical to the biology of CML LSCs. These cells depend on oxidative phosphorylation (OXPHOS) and mitochondrial homeostasis, utilizing fatty acid oxidation as their primary ATP source. Research highlights significant alterations in signaling networks, marked by a dynamic interplay among dominant pathways within the CML clone. While TGF-β-FOXO signaling maintains the self-renewal capacity of quiescent LSCs, proliferating mature CML cells rely heavily on glycolysis and the PI3K/Akt pathway. Furthermore, unique metabolic traits of LSCs underscore the impact of leukemic cell–microenvironment interactions in fostering a permissive niche. Conclusions: Fatty acid oxidation is critical to the survival and self-renewal of CML LSCs. This adaptation of mitochondrial function is closely linked to signaling alterations and entails an adjustment of mitochondrial respiration alongside stimulated OXPHOS. Emerging research unveils many potential targets within metabolic signaling that can be exploited to overcome these survival mechanisms, highlighting the disruption of mitochondrial energy support as a promising strategy to selectively eradicate CML LSCs.