Renner 2017 MiP2017
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.
Labels: MiParea: Pharmacology;toxicology
Organism: Human Tissue;cell: Macrophage-derived
- 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)
- Internal Medicine III, Univ Hospital, Regensburg, Germany
- Dept Internal Medicine 5, Hematology Oncology, Univ Erlangen-Nuremberg, Germany
- Inst Functional Genomics, Univ Regensburg, Germany. - [email protected]