An updated outlook on autophagy mechanism and how it supports acute myeloid leukemia maintenance

• Published in: Biochimica et biophysica acta. Reviews on cancer 2024-11, Vol.1879 (6), p.189214, Article 189214
• Main Authors: Santos de Macedo, Brunno Gilberto, Albuquerque de Melo, Manuela, Pereira-Martins, Diego Antonio, Machado-Neto, João Agostinho, Traina, Fabiola
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Animals; Autophagy; Autophagy - drug effects; Autophagy - genetics; Cell Differentiation; Drug Resistance, Neoplasm; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Leukemic stem cell; Mitochondria - metabolism; Mitochondria - pathology; Mitophagy; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oxidative Stress; Selective autophagy
• ISSN: 0304-419X; 1879-2561; 1879-2561
• DOI: 10.1016/j.bbcan.2024.189214

The gradual acquisition of genetic and epigenetic disturbances bestows malignant traits upon hematopoietic stem cells, subverting them into a founder and reservoir cell for de novo acute myeloid leukemia (AML) known as leukemic stem cells (LSC). Beyond its molecular heterogeneity, AML is also characterized by rewiring biological processes to support its onset and maintenance. LSC were observed to inherently and actively trigger mitochondrial turnover through selective autophagic removal such that impairing the process led to cell differentiation at the expense of its stemness. This review provides a current take on autophagy regulation mechanisms according to the current molecular characterization of the process; describes autophagy as a drug resistance mechanism, and a pivotal mechanism whereby LSC harmonize their strong reliance on mitochondrial respiration to obtain energy, and their necessity for lower internal oxidative stress to avoid exhaustion. Therefore, targeting autophagy presents a promising strategy to promote long-term remissions in AML. [Display omitted] •Autophagy is a key promoter of cell survival and drug resistance in cancer cells.•Leukemic stem cells must coordinate their dependence on oxidative phosphorylation and need for low internal oxidative stress.•Targeting mitochondrial turnover promotes leukemic stem cell exhaustion.•Mitophagy stands as a potential therapy target for acute myeloid leukemia.