Hammon, Kathrin and Renner, Kathrin and Althammer, Michael and Voll, Florian and Babl, Nathalie and Decking, Sonja-Maria and Siska, Peter J. and Matos, Carina and Conejo, Zugey Elizabeth Cardenas and Mendes, Karina and Einwag, Friederike and Siegmund, Heiko and Iberl, Sabine and Berger, Raffaela S. and Dettmer, Katja and Schoenmehl, Rebecca and Brochhausen, Christoph and Herr, Wolfgang and Oefner, Peter J. and Rehli, Michael and Thomas, Simone and Kreutz, Marina (2024) D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells. HAEMATOLOGICA, 109 (8). pp. 2500-2514. ISSN 0390-6078, 1592-8721
Full text not available from this repository. (Request a copy)Abstract
D-2-hydroxyglutarate (D-2-HG) accumulates in patients with acute myeloid leukemia (AML) with mutated isocitrate dehydrogenase (IDH) 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 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 potentially novel therapeutic strategy with combinations of anti-glycolytic drugs and epigenetic modulators (hypomethylating agents) or other therapeutics for the treatment of AML.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LACTATE-DEHYDROGENASE; CANCER-CELLS; MUTATIONS; METABOLISM; IDH1; 2-HYDROXYGLUTARATE; LEUKEMOGENESIS; ACCUMULATION; ACTIVATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Abteilung für Neuropathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Jul 2025 05:34 |
| Last Modified: | 23 Jul 2025 05:34 |
| URI: | https://pred.uni-regensburg.de/id/eprint/63494 |
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