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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 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...

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Hauptverfasser: Hammon, Kathrin (VerfasserIn) , Renner, Kathrin (VerfasserIn) , Althammer, Michael (VerfasserIn) , Voll, Florian (VerfasserIn) , Babl, Nathalie (VerfasserIn) , Decking, Sonja-Maria (VerfasserIn) , Siska, Peter J. (VerfasserIn) , Matos, Carina (VerfasserIn) , Conejo, Zugey Elizabeth Cárdenas (VerfasserIn) , Mendes, Karina (VerfasserIn) , Einwag, Friederike (VerfasserIn) , Siegmund, Heiko (VerfasserIn) , Iberl, Sabine (VerfasserIn) , Berger, Raffaela S. (VerfasserIn) , Dettmer, Katja (VerfasserIn) , Schönmehl, Rebecca (VerfasserIn) , Brochhausen, Christoph (VerfasserIn) , Herr, Wolfgang (VerfasserIn) , Oefner, Peter J. (VerfasserIn) , Rehli, Michael (VerfasserIn) , Thomas, Simone (VerfasserIn) , Kreutz, Marina (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: August, 2024
In: Haematologica
Year: 2024, Jahrgang: 109, Heft: 8, Pages: 2500-2514
ISSN:1592-8721
DOI:10.3324/haematol.2023.283597
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3324/haematol.2023.283597
Verlag, lizenzpflichtig, Volltext: https://haematologica.org/article/view/haematol.2023.283597
Volltext
Verfasserangaben:Kathrin Hammon, Kathrin Renner, Michael Althammer, Florian Voll, Nathalie Babl, Sonja-Maria Decking, Peter J. Siska, Carina Matos, Zugey Elizabeth Cárdenas Conejo, Karina Mendes, Friederike Einwag, Heiko Siegmund, Sabine Iberl, Raffaela S. Berger, Katja Dettmer, Rebecca Schoenmehl, Christoph Brochhausen, Wolfgang Herr, Peter J. Oefner, Michael Rehli, Simone Thomas, Marina Kreutz
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 03.04.2025
Beschreibung:Online Resource
ISSN:1592-8721
DOI:10.3324/haematol.2023.283597

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