ArticleCell death & disease2024
Venetoclax resistance in acute lymphoblastic leukemia is characterized by increased mitochondrial activity and can be overcome by co-targeting oxidative phosphorylation.
Article in Cell death & disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Venetoclax and hypomethylating agents synergize to increase cell death and metabolic remodeling in acute B-lymphoblastic leukemia cells.Molecular metabolism · 2026Article
- Specific FbioRxiv : the preprint server for biology · 2026Article
- Therapeutic potential of BH3-mimetics and NK cell-mediated immunotherapy in T-ALL.Cell death & disease · 2026Article
- A measles virus encoding a CD19/CD3 bispecific T cell engager shows enhanced preclinical anti-BCP-ALL efficacy without significant toxicity.Molecular therapy. Oncology · 2026Article
- The use of venetoclax in the treatment of acute lymphoblastic leukemia-a systematic review.Therapeutic advances in medical oncology · 2026Review
- Venetoclax resistance in preclinical KMT2A-rearranged acute lymphoblastic leukemia models is characterized by high inter- and intra-model heterogeneity.NPJ precision oncology · 2025Article
- Establishment and characterization of a novel cell line ICH-BCPALL-3 from B cell precursor acute lymphoblastic leukemia with TCF3::HLF.Human cell · 2025Article
- Overcoming B-ALL Resistance to Targeted and Immune Therapies by Rational Combination Strategies.Blood cancer discovery · 2025Review
- Mitochondrial Dynamics in Blood Cancer Development and Progression.Current pharmacology reports · 2025Review
- The dual BCL-2 and BCL-XL inhibitor AZD4320 acts on-target and synergizes with MCL-1 inhibition in B-cell precursor ALL.Blood advances · 2024Article
- Saikosaponins Targeting Programmed Cell Death as Anticancer Agents: Mechanisms and Future Perspectives.Drug design, development and therapy · 2024Review
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14 authors.
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Abstract
Deregulated apoptosis signaling is characteristic for many cancers and contributes to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Apoptosis is controlled by different pro- and anti-apoptotic molecules. Inhibition of anti-apoptotic molecules like B-cell lymphoma 2 (BCL-2) has been developed as therapeutic strategy. Venetoclax (VEN), a selective BCL-2 inhibitor has shown clinical activity in different lymphoid malignancies and is currently evaluated in first clinical trials in BCP-ALL. However, insensitivity to VEN has been described constituting a major clinical concern. Here, we addressed and modeled VEN-resistance in BCP-ALL, investigated the underlying mechanisms in cell lines and patient-derived xenograft (PDX) samples and identified potential strategies to overcome VEN-insensitivity. Leukemia lines with VEN-specific resistance were generated in vitro and further characterized using RNA-seq analysis. Interestingly, gene sets annotated to the citric/tricarboxylic acid cycle and the respiratory electron transport chain were significantly enriched and upregulated, indicating increased mitochondrial metabolism in VEN-resistant ALL. Metabolic profiling showed sustained high mitochondrial metabolism in VEN-resistant lines as compared to control lines. Accordingly, primary PDX-ALL samples with intrinsic VEN-insensitivity showed higher oxygen consumption and ATP production rates, further highlighting that increased mitochondrial activity is a characteristic feature of VEN-resistant ALL. VEN-resistant PDX-ALL showed significant higher mitochondrial DNA content and differed in mitochondria morphology with significantly larger and elongated structures, further corroborating our finding of augmented mitochondrial metabolism upon VEN-resistance. Using Oligomycin, an inhibitor of the complex V/ATPase subunit, we found synergistic activity and apoptosis induction in VEN-resistant BCP-ALL cell lines and PDX samples, demonstrating that acquired and intrinsic VEN-insensitivity can be overcome by co-targeting BCL-2 and the OxPhos pathway. These findings of reprogrammed, high mitochondrial metabolism in VEN-resistance and synergistic activity upon co-targeting BCL-2 and oxidative phosphorylation strongly suggest further preclinical and potential clinical evaluation in VEN-resistant BCP-ALL.
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