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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

2024-01-18Journal article Open access
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dc.contributor.authorHammon, Kathrin
dc.contributor.authorRenner, Kathrin
dc.contributor.authorAlthammer, Michael
dc.contributor.authorVoll, Florian
dc.contributor.authorBabl, Nathalie
dc.contributor.authorDecking, Sonja-Maria
dc.contributor.authorSiska, Peter J.
dc.contributor.authorMatos, Carina
dc.contributor.authorConejo, Zugey Elizabeth Cárdenas
dc.contributor.authorMendes, Karina
dc.contributor.authorEinwag, Friederike
dc.contributor.authorSiegmund, Heiko
dc.contributor.authorIberl, Sabine
dc.contributor.authorBerger, Raffaela S.
dc.contributor.authorDettmer, Katja
dc.contributor.authorSchoenmehl, Rebecca
dc.contributor.authorBrochhausen, Christoph
dc.contributor.authorHerr, Wolfgang
dc.contributor.authorOefner, Peter J.
dc.contributor.authorRehli, Michael
dc.contributor.authorThomas, Simone
dc.contributor.authorKreutz, Marina
dc.date.accessioned2024-07-30T14:02:54Z
dc.date.available2024-07-30T14:02:54Z
dc.date.issued2024-01-18
dc.description.abstractD-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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.3324/haematol.2023.283597pt_PT
dc.identifier.eid85200423972
dc.identifier.issn0390-6078
dc.identifier.pmcPMC11290548
dc.identifier.pmid38235501
dc.identifier.urihttp://hdl.handle.net/10400.14/45953
dc.identifier.wos001381323000015
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.titleD-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage2514pt_PT
oaire.citation.startPage2500pt_PT
oaire.citation.titleHaematologicapt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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