http://orcid.org/0000-0003-2911-8830
![Sample our Medicine, Dentistry, Nursing & Allied Health journals, sign in here to start your FREE access for 14 days]({"type":"image" , "src" : "/sda/5944/TOC-Subject-Sample-2021-Medicine-Dentistry-Nursing-Allied-Health.jpg"})
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.
Abbreviations
| 2DG | = | 2-deoxglucose |
| αKG | = | α-ketoglutarate |
| D-2HG | = | D-2-hydroxyglutarate |
| DIP | = | 2’2-dipyridyl |
| ECAR | = | extracellular acidification rate |
| GLUT | = | glucose transporter |
| HD | = | healthy donor |
| HIF-1α | = | hypoxia inducible factor-1α |
| OCR | = | oxygen consumption rate |
| OGT | = | O-linked N-acetylglucosamine (GlcNAc) transferase |
| ROS | = | reactive oxygen species |
| TCA | = | tricarboxylic acid |
| Treg | = | regulatory T-cell |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Author contributions
DM, MB, and MK conceived the project and designed experiments. MB and DM wrote the manuscript. MB and KR designed, conducted, and supervised experiments and analyzed data. KR and MK provided essential intellectual input and contributed to the manuscript. RB and KM conducted experiments and contributed to the manuscript. RB, ST, EZC, KD, and PJO performed experiments, provided essential technical help, and reagents/analytical tools. AM provided intellectual input for project design.
Acknowledgment
We thank Dr. Christina Warnecke for valuable hints regarding HIF-1α stabilization. DM was supported by the IZKF Erlangen Project D27, the Else Kröner-Fresenius-Stiftung, and the CRC/TR221-DFG Project A06. The study was furthermore supported by the KFO262 (DFG).