ArticleMolecular oncology2021
Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia.
Article in Molecular oncology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 44 citations in OpenAlex.
- Functional cooperation between the B-cell receptor and NOTCH1 in regulating metabolic reprogramming in chronic lymphocytic leukemia.Leukemia · 2026Article
- Fueling the Fire: How Glutamine Metabolism Sustains Leukemia Growth and Resistance.BioMed (Basel, Switzerland) · 2026Article
- Maternal supplementation with rumen-protected arginine reshapes the ileal microbiome and enhances neonatal lamb growth.Animal microbiome · 2026Article
- Glutamine alleviates radiation-induced intestinal injury in rats via the mTOR/Notch1 axis.Frontiers in oncology · 2026Article
- Amino acid metabolic reprogramming drives pathogenesis and therapy in hematologic malignancies.Discover oncology · 2025Review
- Peptide Drug: Design and Clinical Applications.MedComm · 2025Review
- Metabolism and signaling crosstalk in glioblastoma progression and therapy resistance.Molecular oncology · 2025Review
- Notch signaling in cancer: metabolic reprogramming and therapeutic implications.Frontiers in immunology · 2025Review
- The glutamate/aspartate transporter EAAT1 is crucial for T-cell acute lymphoblastic leukemia proliferation and survival.Haematologica · 2024Article
- Glutamine and leukemia research: progress and clinical prospects.Discover oncology · 2024Review
- Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal transduction and targeted therapy · 2024Review
- TIM-3/Galectin-9 interaction and glutamine metabolism in AML cell lines, HL-60 and THP-1.BMC cancer · 2024Article
- Comprehensive analysis based on glycolytic and glutaminolytic pathways signature for predicting prognosis and immunotherapy in ovarian cancer.Journal of Cancer · 2024Article
- Dietary Manipulation of Amino Acids for Cancer Therapy.Nutrients · 2023Review
- Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells.International journal of molecular sciences · 2023Article
- Glutamine synthetase expression rescues human dendritic cell survival in a glutamine-deprived environment.Frontiers in oncology · 2023Article
- Formyl-Peptide Receptor 2 Signaling Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming of Lung Cancer Cells.Antioxidants (Basel, Switzerland) · 2022Article
- Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.Nature communications · 2022Article
- Deciphering Metabolic Adaptability of Leukemic Stem Cells.Frontiers in oncology · 2022Review
- The Role of Amino Acids in the Crosstalk Between Mesenchymal Stromal Cells and Neoplastic Cells in the Hematopoietic Niche.Frontiers in cell and developmental biology · 2021Review
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Authors and funding
25 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The cellular receptor Notch1 is a central regulator of T-cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T-cell acute lymphoblastic leukemia (T-ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T-ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti-Notch therapies in T-ALL models. In this work, we report that Notch1 upregulation in T-ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1-driven T-ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1-induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1-driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1-driven leukemia.
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