Targeting Mitochondrial Vulnerabilities in Chronic Myeloid Leukemia: From Pathobiology to Novel Therapeutic Opportunities

TL;DR

This paper reviews how mitochondrial dysfunction contributes to chronic myeloid leukemia and explores new therapies targeting mitochondria to improve treatment outcomes.

Contribution

The paper systematically reviews mitochondrial alterations in CML and proposes novel therapeutic strategies targeting mitochondrial function.

Findings

Mitochondrial dysfunction supports CML progression and drug resistance.

Altered mitochondrial metabolism and ROS signaling promote leukemogenesis and genomic instability.

Targeting mitochondrial pathways could overcome tyrosine kinase inhibitor resistance in CML.

Abstract

Chronic myeloid leukemia (CML) is a blood cancer characterized by metabolic defects, including dysregulated energy management, impaired redox balance, and resistance to programmed cell death. Central to these processes are mitochondria, as essential regulators of cellular energy production, survival, and apoptosis. In CML, mitochondrial dysfunction supports disease progression and contributes to therapeutic resistance. This review highlights the role of altered mitochondrial biology in CML pathogenesis and explores potential therapeutic strategies that target mitochondrial function as a means to enhance treatment efficacy and overcome drug resistance.

Background: Mitochondria are multifunctional organelles that play a central role in maintaining cellular homeostasis by regulating energy metabolism, reactive oxygen species (ROS) generation, ion homeostasis, and apoptotic signaling. Dynamic processes such as mitochondrial fission, fusion, and intracellular trafficking enable cells to adapt to metabolic and environmental stress. Growing evidence indicates that dysregulation of these processes is a hallmark of cancer, contributing to metabolic reprogramming, redox imbalance, evasion of apoptosis, and disease progression. This narrative review aims to discuss the role of mitochondrial alterations in the pathophysiology of chronic myeloid leukemia (CML) and their potential therapeutic implications. Methods: Original research articles published between 2010 and 2025 were considered in this narrative review. The selected studies were critically discussed and categorized into three principal thematic domains: mitochondrial regulation of redox homeostasis, metabolic rewiring, and control of cell death pathways. Evidence was synthesized to elucidate the contribution of mitochondrial dysfunction to CML initiation, progression, and therapeutic resistance. Results: The reviewed studies highlight how mitochondrial abnormalities play a pivotal role in BCR-ABL1-driven leukemogenesis. Alterations in mitochondrial metabolism and ROS signaling support sustained proliferative signaling, promote genomic instability, and facilitate resistance to apoptosis. In addition, mitochondrial adaptations contribute to resistance to tyrosine kinase inhibitors (TKIs) and are essential for the persistence and survival of leukemic stem cells. Conclusions: Mitochondria emerge as central regulators of CML pathobiology. Therapeutic strategies targeting mitochondrial metabolism, redox homeostasis, and apoptotic signaling pathways represent promising approaches to overcoming TKI resistance and may improve clinical outcomes for patients with CML.

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