Renner 2017 MiP2017

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Kathrin Renner-Sattler
D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization.

Link: MiP2017

Renner K, Boettcher M, Berger R, Mentz K, Thomas S, Zugey Cadenas E, Dettmer K, Oefner P, Mackensen A, Kreutz M, Mougiakakos D (2017)

Event: MiP2017

COST Action MITOEAGLE
D-2-hydroxyglutarate (D-2HG) is abundantly released by various types of malignant cells such as 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. As anticipated, IDH mutations and high D-2HG levels are associated with inferior prognosis in AML. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion. However, impact of D-2HG on immune cells remains unexplored. Here, we sought out to investigate the effects of D-2HG on T-cells as key mediators of the anti-AML immunity. D-2HG is efficiently taken up by T-cells, which is in line with the high 2-HG levels that we occasionally measured in AML patient-derived T-cells. During our short-term cultures we did not observe detrimental effects on responsiveness towards activating stimuli. We noticed a D-2HG-triggered HIF-1α protein destabilization linked to metabolic skewing towards oxidative phosphorylation and reduced T helper 17 (Th17) cell polarization. In line with these findings, IL-17 and Rorγ(t), the prototypical Th17 cell transcription factor, were found decreased in AML patient-derived T-cells suggesting for the first time that D-2HG might contribute to fine tuning of immune responses.


Bioblast editor: Kandolf G O2k-Network Lab: DE Regensburg Renner-Sattler K


Labels: MiParea: Pharmacology;toxicology 


Organism: Human  Tissue;cell: Macrophage-derived 





Affiliations

Renner K(1), Boettcher M(2), Berger R(3), Mentz K(2), Thomas S(1), Zugey Cadenas E(1), Dettmer K(3), Oefner P(3), Mackensen A(2), Kreutz M(1), Mougiakakos D(2)
  1. Internal Medicine III, Univ Hospital, Regensburg, Germany
  2. Dept Internal Medicine 5, Hematology Oncology, Univ Erlangen-Nuremberg, Germany
  3. Inst Functional Genomics, Univ Regensburg, Germany. - kathrin.renner-sattler@ukr.de