Author(s):
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Lith, S.A.M. van;
Navis, A.C.
;
Lenting, K.
;
Verrijp, K.
;
Schepens, J.T.G.
;
Hendriks, W.J.A.J.
; Schubert, N.A.;
Venselaar, H.
;
Wevers, R.A.
;
Rooij, A.J. van
;
Wesseling, P.
; Molenaar, R.J.; Noorden, C.J.F. van; Pusch, S.; Tops, B.;
Leenders, W.P.J.
|
Subject:
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Radboudumc 19: Nanomedicine RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience Radboudumc 9: Rare cancers RIMLS: Radboud Institute for Molecular Life Sciences |
Organization:
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Pathology Cell Biology (UMC) CMBI Paediatrics - OUD tm 2017 Laboratory Medicine Laboratory of Genetic, Endocrine and Metabolic Diseases |
Abstract:
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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 (alpha-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce alpha-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of alpha-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 alpha-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-alpha-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 alpha-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.
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