D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells
D-2-hydroxyglutarate (D-2-HG) accumulates in primary acute myeloid leukemia (AML) patients with mutated isocitrate dehydrogenase (IDH) and 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 (DC) differentiation, resulting in a tolerogenic phenotype with low major histocompatibility (MHC) class II expression. In line, IDH-mutated AML blasts exhibited lower expression of HLA-DP and were less susceptible to lysis by HLA-DP-specific T cells. Interestingly, D-2-HG reprogrammed metabolism towards increased lactate production in DCs and AML besides its expected impact on DNA demethylation. Vitamin C accelerated DNA demethylation, but only the combination of vitamin C and glycolytic inhibition lowered lactate levels and supported MHC 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Haematologica - (2024) vom: 18. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hammon, Kathrin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 18.01.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.3324/haematol.2023.283597 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367260085 |
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| 245 | 1 | 0 | |a D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells |
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| 520 | |a D-2-hydroxyglutarate (D-2-HG) accumulates in primary acute myeloid leukemia (AML) patients with mutated isocitrate dehydrogenase (IDH) and 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 (DC) differentiation, resulting in a tolerogenic phenotype with low major histocompatibility (MHC) class II expression. In line, IDH-mutated AML blasts exhibited lower expression of HLA-DP and were less susceptible to lysis by HLA-DP-specific T cells. Interestingly, D-2-HG reprogrammed metabolism towards increased lactate production in DCs and AML besides its expected impact on DNA demethylation. Vitamin C accelerated DNA demethylation, but only the combination of vitamin C and glycolytic inhibition lowered lactate levels and supported MHC 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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| 700 | 1 | |a Renner, Kathrin |e verfasserin |4 aut | |
| 700 | 1 | |a Althammer, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Voll, Florian |e verfasserin |4 aut | |
| 700 | 1 | |a Babl, Nathalie |e verfasserin |4 aut | |
| 700 | 1 | |a Decking, Sonja-Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Siska, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Matos, Carina |e verfasserin |4 aut | |
| 700 | 1 | |a Conejo, Zugey Elizabeth Cárdenas |e verfasserin |4 aut | |
| 700 | 1 | |a Mendes, Karina |e verfasserin |4 aut | |
| 700 | 1 | |a Einwag, Friederike |e verfasserin |4 aut | |
| 700 | 1 | |a Siegmund, Heiko |e verfasserin |4 aut | |
| 700 | 1 | |a Iberl, Sabine |e verfasserin |4 aut | |
| 700 | 1 | |a Berger, Raffaela S |e verfasserin |4 aut | |
| 700 | 1 | |a Dettmer, Katja |e verfasserin |4 aut | |
| 700 | 1 | |a Schoenmehl, Rebecca |e verfasserin |4 aut | |
| 700 | 1 | |a Brochhausen, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Herr, Wolfgang |e verfasserin |4 aut | |
| 700 | 1 | |a Oefner, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Rehli, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Simone |e verfasserin |4 aut | |
| 700 | 1 | |a Kreutz, Marina |e verfasserin |4 aut | |
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