ArticleBlood advances2021
Inhibiting autophagy targets human leukemic stem cells and hypoxic AML blasts by disrupting mitochondrial homeostasis.
Article in Blood advances, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 49 citations in OpenAlex.
- Article
- Translational insights and clinical challenges of targeting cancer stem cells.Signal transduction and targeted therapy · 2026Review
- Autophagy and Lipid Metabolism as a Therapeutic Target for Overcoming Drug Resistance in Acute Myeloid Leukemia.Life (Basel, Switzerland) · 2026Review
- Venetoclax induces mitochondrial apoptosis and autophagy to overcome arsenic trioxide resistance in acute promyelocytic leukemia.Journal of translational medicine · 2026Article
- Integrating multi-omics and network toxicology to identify FIS1 as a key target of environmental pollutants in male infertility.Frontiers in cell and developmental biology · 2026Article
- One size does not fit all: A comparative framework for optimizing ribonucleic acid transfection across acute myeloid leukemia cell lines.Biology methods & protocols · 2026Article
- Inhibition of PI3K/AKT/mTOR signaling enhances autophagy in HL-60 acute myeloid leukemia cells: An integrative bioinformatic and in vitro study.Biochemistry and biophysics reports · 2025Article
- Retrograde rearrangement of mitochondria correlates with nuclear deformation and genotoxic damage.iScience · 2025Article
- Mitochondrial FIS1 As a Novel Drug Target for the Treatment of Erectile Dysfunction: A Multi-Omic and Epigenomic Association Study.The world journal of men's health · 2025Article
- Mitochondrial quality control in hematopoietic stem cells: mechanisms, implications, and therapeutic opportunities.Stem cell research & therapy · 2025Review
- Hypoxia-Induced Metabolic and Functional Changes in Oral CSCs: Implications for Stemness and Viability Modulation Through BNIP3-Driven Mitophagy.Journal of cellular and molecular medicine · 2025Article
- Identification of the prognostic effect of mitophagy-related genes in acute myeloid leukemia.Frontiers in immunology · 2025Article
- Current Understanding of the Role of Autophagy in the Treatment of Myeloid Leukemia.International journal of molecular sciences · 2024Review
- High Mitophagy and Low Glycolysis Predict Better Clinical Outcomes in Acute Myeloid Leukemias.International journal of molecular sciences · 2024Article
- UNC13B regulates the sensitivity of Wilms' tumor cells to doxorubicin by modulating lysosomes.Oncology letters · 2024Article
- A mitochondrial surveillance mechanism activated bybioRxiv : the preprint server for biology · 2024Article
- Review
- Crosstalk between autophagy and metabolism: implications for cell survival in acute myeloid leukemia.Cell death discovery · 2024Review
- Targeting Lysosomes: A Strategy Against Chemoresistance in Cancer.Mini reviews in medicinal chemistry · 2024Review
- Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.Frontiers in oncology · 2024Review
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Leukemia stem cells (LSCs) and therapy-resistant acute myeloid leukemia (AML) blasts contribute to the reinitiation of leukemia after remission, necessitating therapeutic interventions that target these populations. Autophagy is a prosurvival process that allows for cells to adapt to a variety of stressors. Blocking autophagy pharmacologically by using mechanistically distinct inhibitors induced apoptosis and prevented colony formation in primary human AML cells. The most effective inhibitor, bafilomycin A1 (Baf A1), also prevented the in vivo maintenance of AML LSCs in NSG mice. To understand why Baf A1 exerted the most dramatic effects on LSC survival, we evaluated mitochondrial function. Baf A1 reduced mitochondrial respiration and stabilized PTEN-induced kinase-1 (PINK-1), which initiates autophagy of mitochondria (mitophagy). Interestingly, with the autophagy inhibitor chloroquine, levels of enhanced cell death and reduced mitochondrial respiration phenocopied the effects of Baf A1 only when cultured in hypoxic conditions that mimic the marrow microenvironment (1% O2). This indicates that increased efficacy of autophagy inhibitors in inducing AML cell death can be achieved by concurrently inducing mitochondrial damage and mitophagy (pharmacologically or by hypoxic induction) and blocking mitochondrial degradation. In addition, prolonged exposure of AML cells to hypoxia induced autophagic flux and reduced chemosensitivity to cytarabine (Ara-C), which was reversed by autophagy inhibition. The combination of Ara-C with Baf A1 also decreased tumor burden in vivo. These findings demonstrate that autophagy is critical for mitochondrial homeostasis and survival of AML cells in hypoxia and support the development of autophagy inhibitors as novel therapeutic agents for AML.
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