title: Metabolic reprogramming in mutant IDH1 glioma cells.
abstract: BACKGROUND
  Mutations in isocitrate dehydrogenase (IDH) 1 have been reported in over 70% of low-grade gliomas and secondary glioblastomas. IDH1 is the enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate while mutant IDH1 catalyzes the conversion of α-ketoglutarate into 2-hydroxyglutarate. These mutations are associated with the accumulation of 2-hydroxyglutarate within the tumor and are believed to be one of the earliest events in the development of low-grade gliomas. The goal of this work was to determine whether the IDH1 mutation leads to additional magnetic resonance spectroscopy (MRS)-detectable changes in the cellular metabolome.
  
  
  METHODS
  Two genetically engineered cell models were investigated, a U87-based model and an E6/E7/hTERT immortalized normal human astrocyte (NHA)-based model. For both models, wild-type IDH1 cells were generated by transduction with a lentiviral vector coding for the wild-type IDH1 gene while mutant IDH1 cells were generated by transduction with a lentiviral vector coding for the R132H IDH1 mutant gene. Metabolites were extracted from the cells using the dual-phase extraction method and analyzed by 1H-MRS. Principal Component Analysis was used to analyze the MRS data.
  
  
  RESULTS
  Principal Component Analysis clearly discriminated between wild-type and mutant IDH1 cells. Analysis of the loading plots revealed significant metabolic changes associated with the IDH1 mutation. Specifically, a significant drop in the concentration of glutamate, lactate and phosphocholine as well as the expected elevation in 2-hydroxyglutarate were observed in mutant IDH1 cells when compared to their wild-type counterparts.
  
  
  CONCLUSIONS
  The IDH1 mutation leads to several, potentially translatable MRS-detectable metabolic changes beyond the production of 2-hydroxyglutarate.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Izquierdo-Garcia
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Pavithra
authors.initials: P
authors.lastname: Viswanath
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Pia
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Myriam M
authors.initials: MM
authors.lastname: Chaumeil
authors.affiliation: Department of Neurological Surgery, Helen Diller Research Center, University of California San Francisco, San Francisco, California, United States of America; Brain Tumor Research Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
authors.affiliation: Department of Neurological Surgery, Helen Diller Research Center, University of California San Francisco, San Francisco, California, United States of America; Brain Tumor Research Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America; Brain Tumor Research Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Ronen
mesh_terms: D001932:Brain Neoplasms / Q000201:enzymology*; D005909:Glioblastoma / Q000201:enzymology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000378:metabolism*; D009154:Mutation
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human