Boettcher, Martin and Renner, Kathrin and Berger, Raffaela and Mentz, Kristin and Thomas, Simone and Cardenas-Conejo, Zugey Elizabeth and Dettmer, Katja and Oefner, Peter J. and Mackensen, Andreas and Kreutz, Marina and Mougiakakos, Dimitrios (2018) D-2-hydroxyglutarate interferes with HIF-1 stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization. ONCOIMMUNOLOGY, 7 (7): e1445454. ISSN 2162-402X,
Full text not available from this repository. (Request a copy)Abstract
D-2-hydroxyglutarate (D-2HG) is released by various types of malignant cells including acute myeloid leukemia (AML) blasts carrying isocitrate dehydrogenase (IDH) gain-of-function mutations. D-2HG acting as an oncometabolite promotes proliferation, anoikis, and differentiation block of hematopoietic cells in an autocrine fashion. However, prognostic impact of IDH mutations and high D-2HG levels remains controversial and might depend on the overall mutational context. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion. Impact of D-2HG on immune cells remains incompletely understood. Here, we sought out to investigate the effects of D-2HG on T-cells as key mediators of anti-AML immunity. D-2HG was efficiently taken up by T-cells in vitro, which is in line with high 2-HG levels measured in T-cells isolated from AML patients carrying IDH mutations. T-cell activation was slightly impacted by D-2HG. However, D-2HG triggered HIF-1a protein destabilization resulting in metabolic skewing towards oxidative phosphorylation, increased regulatory T-cell (Treg) frequency, and reduced T helper 17 (Th17) polarization. Our data suggest for the first time that D-2HG might contribute to fine tuning of immune responses.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOID-LEUKEMIA; ISOCITRATE DEHYDROGENASE MUTATIONS; MITOCHONDRIAL OXYGEN-CONSUMPTION; HYPOXIA-INDUCIBLE FACTOR; MAMMALIAN TARGET; IDH2 MUTATIONS; ONCOMETABOLITE 2-HYDROXYGLUTARATE; AEROBIC GLYCOLYSIS; RAPAMYCIN MTOR; DIFFERENTIATION; immunometabolism; oncometabolite; acute myeloid leukemia; IDH mutation; Th17; Tregs; 2HG; Immunosurveillance; Inflammation and cancer |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Mar 2020 10:35 |
| Last Modified: | 20 Mar 2020 10:35 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15378 |
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