ArticleHaematologica2024
D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells.
Article in Haematologica, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 13 citations in OpenAlex.
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- Immunometabolism: crosstalk with tumor metabolism and implications for cancer immunotherapy.Molecular cancer · 2025Review
- Metabolites as agents and targets for cancer immunotherapy.Nature reviews. Drug discovery · 2025Review
- Glycolysis-Driven Prognostic Model for Acute Myeloid Leukemia: Insights into the Immune Landscape and Drug Sensitivity.Biomedicines · 2025Article
- Metabolic reprogramming and immune regulation in acute myeloid leukemia.Frontiers in immunology · 2025Review
- The interaction between common genetic mutations in AML and the immune landscape: mechanisms and implications for immune response.Frontiers in immunology · 2025Review
- Optimizing CD8Experimental hematology & oncology · 2024Review
- Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin.International journal of molecular sciences · 2024Review
- Targeting glycolysis to rescue 2-hydroxyglutarate immunosuppressive effects in dendritic cells and acute myeloid leukemia.Haematologica · 2024Article
- Article
- Metabolic instruction of the graft-versus-leukemia immunity.Frontiers in immunology · 2024Review
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Authors and funding
22 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
D-2-hydroxyglutarate (D-2-HG) accumulates in patients with acute myeloid leukemia (AML) with mutated isocitrate dehydrogenase (IDH) and in other malignancies. D-2-HG suppresses antitumor T-cell immunity but little is known about potential effects on non-malignant myeloid cells. Here we show that D-2-HG impairs human but not murine dendritic cell differentiation, resulting in a tolerogenic phenotype with low major histocompatibility class II expression. In line with this, IDH-mutated AML blasts exhibited lower expression of HLA-DP and were less susceptible to lysis by HLA-DP-specific T cells. Interestingly, besides its expected impact on DNA demethylation, D-2-HG reprogrammed metabolism towards increased lactate production in dendritic cells and AML. Vitamin C accelerated DNA demethylation, but only the combination of vitamin C and glycolytic inhibition lowered lactate levels and supported major histocompatibility complex class II expression. Our results indicate an unexpected link between the immunosuppressive metabolites 2-HG and lactic acid and suggest a potentially novel therapeutic strategy with combinations of anti-glycolytic drugs and epigenetic modulators (hypomethylating agents) or other therapeutics for the treatment of AML.
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