| Autor: |
van Lith SA; Department of Pathology, Radboudumc, Nijmegen, The Netherlands., Navis AC; Department of Pathology, Radboudumc, Nijmegen, The Netherlands., Lenting K; Department of Pathology, Radboudumc, Nijmegen, The Netherlands., Verrijp K; Department of Pathology, Radboudumc, Nijmegen, The Netherlands., Schepens JT; Department of Cell Biology, Radboud Institute for Molecular Life Sciences, The Netherlands., Hendriks WJ; Department of Cell Biology, Radboud Institute for Molecular Life Sciences, The Netherlands., Schubert NA; Department of Pathology, Radboudumc, Nijmegen, The Netherlands., Venselaar H; Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, The Netherlands., Wevers RA; Translational Metabolic Laboratory, Department Laboratory Medicine, Radboudumc, Nijmegen, The Netherlands., van Rooij A; Translational Metabolic Laboratory, Department Laboratory Medicine, Radboudumc, Nijmegen, The Netherlands., Wesseling P; Department of Pathology, Radboudumc, Nijmegen, The Netherlands.; Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands., Molenaar RJ; Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands., van Noorden CJ; Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands., Pusch S; Clinical Cooperation Unit Neuropathology, German Cancer Center (DKFZ), Heidelberg, Germany., Tops B; Department of Pathology, Radboudumc, Nijmegen, The Netherlands., Leenders WP; Department of Pathology, Radboudumc, Nijmegen, The Netherlands. |
| Abstrakt: |
The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (α-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce α-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of α-KG-dependent enzymes that are involved in metabolism and epigenetic regulation. However, much less is known about the implications of the metabolic stress, imposed by decreased α-KG and NADPH production, for tumor biology. We here present a novel heterozygous IDH1 mutation, IDH1(R314C), which was identified by targeted next generation sequencing of a high grade glioma from which a mouse xenograft model and a cell line were generated. IDH1(R314C) lacks isocitrate-to-α-KG conversion activity due to reduced affinity for NADP(+), and differs from the IDH1(R132) mutants in that it does not produce D-2-HG. Because IDH1(R314C) is defective in producing α-KG and NADPH, without concomitant production of the D-2-HG, it represents a valuable tool to study the effects of IDH1-dysfunction on cellular metabolism in the absence of this oncometabolite. |
