Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia

• Published in: Leukemia 2022-01, Vol.36 (1), p.1-12
• Main Authors: de Beauchamp, Lucie, Himonas, Ekaterini, Helgason, G. Vignir
• Format: Article
• Language: English
• Subjects: 631/67/1990/283; 631/67/2327; 631/67/71; Acute myeloid leukemia; Adaptation; Animals; Antineoplastic Agents - pharmacology; Cancer Research; Critical Care Medicine; Disease resistance; Drug development; Drug metabolism; Drug resistance; Energy Metabolism; Health services; Hematology; Humans; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Medicine; Medicine & Public Health; Metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; Oxidative Phosphorylation; Phosphorylation; Review; Review Article; Stem cells; Therapeutic applications; Therapeutic targets; Treatment resistance
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01416-w

While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these diseases, limitations remain. These become apparent when looking at the frequency of treatment resistance leading to disease relapse in leukaemia patients. Key questions regarding the fundamental biology of the leukaemic cells, such as their metabolic dependencies, are still unresolved. Even though a majority of leukaemic cells are killed during initial treatment, persistent leukaemic stem cells (LSCs) and therapy-resistant cells are still not eradicated with current treatments, due to various mechanisms that may contribute to therapy resistance, including cellular metabolic adaptations. In fact, recent studies have shown that LSCs and treatment-resistant cells are dependent on mitochondrial metabolism, hence rendering them sensitive to inhibition of mitochondrial oxidative phosphorylation (OXPHOS). As a result, rewired energy metabolism in leukaemic cells is now considered an attractive therapeutic target and the significance of this process is increasingly being recognised in various haematological malignancies. Therefore, identifying and targeting aberrant metabolism in drug-resistant leukaemic cells is an imperative and a relevant strategy for the development of new therapeutic options in leukaemia. In this review, we present a detailed overview of the most recent studies that present experimental evidence on how leukaemic cells can metabolically rewire, more specifically the importance of OXPHOS in LSCs and treatment-resistant cells, and the current drugs available to target this process. We highlight that uncovering specific energy metabolism dependencies will guide the identification of new and more targeted therapeutic strategies for myeloid leukaemia.