ArticleBlood advances2024
The glutaminase inhibitor CB-839 targets metabolic dependencies of JAK2-mutant hematopoiesis in MPN.
Article in Blood advances, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 17 citations in OpenAlex.
- Unraveling the role of glutamine metabolism in cancer: from cell death mechanisms to tumor microenvironment modulation.Experimental hematology & oncology · 2026Review
- Thrombopoietin Receptor MPL in Hematopoiesis and Myeloproliferative Neoplasms: Physiological Roles and Pathogenic Mechanisms.Stem cell reviews and reports · 2026Review
- Glucose transport dependency defines a therapeutic vulnerability in JAK2V617F-driven myeloproliferative neoplasms.Cell communication and signaling : CCS · 2026Article
- Glutaminase 1 in Vascular Disease: Linking Metabolic Reprogramming to Atherosclerosis Progression and Stability.Journal of cardiovascular translational research · 2026Review
- Fueling the Fire: How Glutamine Metabolism Sustains Leukemia Growth and Resistance.BioMed (Basel, Switzerland) · 2026Article
- Glutamine Metabolism: Role in Cancer Cell Proliferation and Survival.Cancer treatment and research · 2026Review
- The application of nanotechnology in regulating mitochondrial function in tumor microenvironment for cancer therapy.Theranostics · 2026Review
- The role of glutamine metabolism in the pathogenesis of idiopathic pulmonary fibrosis and its therapeutic potential.Frontiers in oncology · 2026Review
- Targeting the Glutaminolysis Pathway in Glaucoma-Associated Fibrosis.International journal of molecular sciences · 2025Review
- Article
- Ammonia metabolism and ammonia-induced cell death: role in cancer therapy.Cell communication and signaling : CCS · 2025Review
- Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.Scientific reports · 2025Article
- Magnetic resonance spectroscopy-based detection of response to therapy targeting glutaminolysis in lymphoma.Blood neoplasia · 2025Article
- Targeting glutamine metabolism as a potential target for cancer treatment.Journal of experimental & clinical cancer research : CR · 2025Review
- Pathogenesis and management of high molecular risk myeloproliferative neoplasms.Haematologica · 2025Review
- Metabolic crossroads: unravelling immune cell dynamics in gastrointestinal cancer drug resistance.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Advances in the study of reversing tumor drug resistance by targeting cancer-associated fibroblasts with nanomaterials.Frontiers in immunology · 2025Review
- DARS expression in BCR/ABL1-negative myeloproliferative neoplasms and its association with the immune microenvironment.Scientific reports · 2024Article
- Targeting metabolic dependencies in JAK2-V617F-driven MPNs.Blood advances · 2024Article
- Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells.Cancer biomarkers : section A of Disease markers · 2024Article
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
abstractHyperproliferation of myeloid and erythroid cells in myeloproliferative neoplasms (MPN) driven by the JAK2-V617F mutation is associated with altered metabolism. Given the central role of glutamine in anabolic and catabolic pathways, we examined the effects of pharmacologically inhibiting glutaminolysis, that is, the conversion of glutamine (Gln) to glutamate (Glu), using CB-839, a small molecular inhibitor of the enzyme glutaminase (GLS). We show that CB-839 strongly reduced the mitochondrial respiration rate of bone marrow cells from JAK2-V617F mutant (VF) mice, demonstrating a marked dependence of these cells on Gln-derived ATP production. Consistently, in vivo treatment with CB-839 normalized blood glucose levels, reduced splenomegaly and decreased erythrocytosis in VF mice. These effects were more pronounced when CB-839 was combined with the JAK1/2 inhibitor ruxolitinib or the glycolysis inhibitor 3PO, indicating possible synergies when cotargeting different metabolic and oncogenic pathways. Furthermore, we show that the inhibition of glutaminolysis with CB-839 preferentially lowered the proportion of JAK2-mutant hematopoietic stem cells (HSCs). The total number of HSCs was decreased by CB-839, primarily by reducing HSCs in the G1 phase of the cell cycle. CB-839 in combination with ruxolitinib also strongly reduced myelofibrosis at later stages of MPN. In line with the effects shown in mice, proliferation of CD34+ hematopoietic stem and progenitor cells from polycythemia vera patients was inhibited by CB-839 at nanomolar concentrations. These data suggest that inhibiting GLS alone or in combination with inhibitors of glycolysis or JAK2 inhibitors represents an attractive new therapeutic approach to MPN.
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