ArticleCancers2022
α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting.
Article in Cancers, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
11 citing papers in PubMed, 11 citations in OpenAlex.
- Spatiotemporal heterogeneity of neutrophil extracellular traps in hepatocellular carcinoma microenvironment and targeted therapy progress.Journal of translational medicine · 2026Review
- Mitochondrial transfer-mediated metabolic reprogramming and drug resistance in bone metastasis: mechanisms and therapeutic strategies.Frontiers in immunology · 2026Review
- Succinylation in cancer immunotherapy: mechanisms, biomarkers, and therapeutic implications.Frontiers in immunology · 2026Review
- Nuclear-localized metabolic enzymes: emerging key players in tumor epigenetic regulation.Molecular and cellular biochemistry · 2025Review
- The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.International journal of molecular sciences · 2024Review
- A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease.Nature communications · 2023Article
- Multi-stage nuclear transcriptomic insights of morphogenesis and biparental role changes in Lentinula edodes.Applied microbiology and biotechnology · 2023Article
- Metabolic Adjustments following Glutaminase Inhibition by CB-839 in Glioblastoma Cell Lines.Cancers · 2023Article
- Targeted Epigenetic Interventions in Cancer with an Emphasis on Pediatric Malignancies.Biomolecules · 2022Review
- Prognostic Significance of Cuproptosis-Related Gene Signatures in Breast Cancer Based on Transcriptomic Data Analysis.Cancers · 2022Article
- The α-Ketoglutarate Dehydrogenase Complex as a Hub of Plasticity in Neurodegeneration and Regeneration.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Despite the development of metabolism-based therapy for a variety of malignancies, resistance to single-agent treatment is common due to the metabolic plasticity of cancer cells. Improved understanding of how malignant cells rewire metabolic pathways can guide the rational selection of combination therapy to circumvent drug resistance. Here, we show that human T-ALL cells shift their metabolism from oxidative decarboxylation to reductive carboxylation when the TCA cycle is disrupted. The α-ketoglutarate dehydrogenase complex (KGDHC) in the TCA cycle regulates oxidative decarboxylation by converting α-ketoglutarate (α-KG) to succinyl-CoA, while isocitrate dehydrogenase (IDH) 1 and 2 govern reductive carboxylation. Metabolomics flux analysis of T-ALL reveals enhanced reductive carboxylation upon genetic depletion of the E2 subunit of KGDHC, dihydrolipoamide-succinyl transferase (DLST), mimicking pharmacological inhibition of the complex. Mechanistically, KGDHC dysfunction causes increased demethylation of nuclear DNA by α-KG-dependent dioxygenases (e.g., TET demethylases), leading to increased production of both IDH1 and 2. Consequently, dual pharmacologic inhibition of the TCA cycle and TET demethylases demonstrates additive efficacy in reducing the tumor burden in zebrafish xenografts. These findings provide mechanistic insights into how T-ALL develops resistance to drugs targeting the TCA cycle and therapeutic strategies to overcome this resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.