title: Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2.
abstract: OBJECTIVE
  IDH1/2 mutations occur in up to 70% of low-grade gliomas and secondary glioblastomas. Mutation of these enzymes reduces the wildtype function of the enzyme (conversion of isocitrate to α-ketoglutarate) while conferring a new enzymatic function, the production of D-2-hydroxyglutarate (D-2-HG) from α-ketoglutarate (α-KG). However, it is unclear how these enzymatic changes contribute to tumorigenesis. Here, we discuss the recent studies that demonstrate how IDH1/2 mutation may alter the metabolism and epigenome of gliomas, how these changes may contribute to tumor formation, and opportunities they might provide for molecular targeting.
  
  
  RESULTS
  Metabolomic studies of IDH1/2 mutant cells have revealed alterations in glutamine, fatty acid, and citrate synthesis pathways. Additionally, D-2-HG produced by IDH1/2 mutant cells can competitively inhibit α-KG-dependent enzymes, including histone demethylases and DNA hydroxylases, potentially leading to a distinct epigenetic phenotype. Alterations in metabolism and DNA methylation present possible mechanisms of tumorigenesis.
  
  
  CONCLUSIONS
  Recent attempts to improve outcomes for glioma patients have resulted in incremental gains. Studies of IDH1/2 mutations have provided mechanistic insights into tumorigenesis and potential avenues for therapeutic intervention. Further study of IDH1/2 mutations might allow for improved therapeutic strategies.
authors.affiliation: Ludwig Collaborative Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Borodovsky
authors.forename: Meghan J
authors.initials: MJ
authors.lastname: Seltzer
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation / Q000502:physiology*
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
references.citation: Clin Cancer Res. 2009 Nov 1;15(21):6479-83
references.pmid: 19861459
references.citation: Cancer Cell. 2005 Jan;7(1):77-85
references.pmid: 15652751
references.citation: J Neurooncol. 2009 Jan;91(2):233-6
references.pmid: 18931888
references.citation: Acta Neuropathol. 2010 Aug;120(2):261-7
references.pmid: 20514489
references.citation: Blood. 2010 Jul 29;116(4):614-6
references.pmid: 20421455
references.citation: Genet Med. 2008 Nov;10(11):767-77
references.pmid: 18941420
references.citation: Cancer Cell. 2011 Jan 18;19(1):17-30
references.pmid: 21251613
references.citation: N Engl J Med. 2009 Sep 10;361(11):1058-66
references.pmid: 19657110
references.citation: Science. 2010 Oct 15;330(6002):336
references.pmid: 20847235
references.citation: Science. 2009 Apr 10;324(5924):261-5
references.pmid: 19359588
references.citation: Leukemia. 2010 Jul;24(7):1283-9
references.pmid: 20485371
references.citation: N Engl J Med. 2009 Feb 19;360(8):765-73
references.pmid: 19228619
references.citation: J Pathol. 2011 Jul;224(3):334-43
references.pmid: 21598255
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3270-5
references.pmid: 21289278
references.citation: J Neurooncol. 2011 Nov;105(2):219-24
references.pmid: 21516462
references.citation: Br J Cancer. 2011 Mar 15;104(6):968-70
references.pmid: 21326241
references.citation: J Pediatr Hematol Oncol. 2009 Nov;31(11):865-9
references.pmid: 19779379
references.citation: J Exp Med. 2010 Feb 15;207(2):339-44
references.pmid: 20142433
references.citation: Haematologica. 2010 Oct;95(10):1668-74
references.pmid: 20494930
references.citation: Mol Cell Biol. 2007 May;27(9):3282-9
references.pmid: 17325041
references.citation: Cancer Cell. 2010 May 18;17(5):510-22
references.pmid: 20399149
references.citation: Cancer Cell. 2010 Mar 16;17(3):225-34
references.pmid: 20171147
references.citation: Cell Metab. 2008 Jan;7(1):11-20
references.pmid: 18177721
references.citation: Science. 2008 Sep 26;321(5897):1807-12
references.pmid: 18772396
references.citation: Hum Mutat. 2010 Mar;31(3):279-83
references.pmid: 20020533
references.citation: Oncotarget. 2010 Nov;1(7):552-62
references.pmid: 21317451
references.citation: Neurology. 2004 May 25;62(10):1882-4
references.pmid: 15159502
references.citation: Nat Med. 1999 Dec;5(12):1396-402
references.pmid: 10581082
references.citation: EMBO Rep. 2011 May;12(5):463-9
references.pmid: 21460794
references.citation: Acta Neuropathol. 2011 Feb;121(2):279-81
references.pmid: 21181477
references.citation: Am J Hum Genet. 2005 Feb;76(2):358-60
references.pmid: 15609246
references.citation: Cancer Res. 2009 Aug 15;69(16):6660-7
references.pmid: 19654296
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Nature. 2009 Dec 10;462(7274):739-44
references.pmid: 19935646
references.citation: Cell Res. 2010 Nov;20(11):1188-200
references.pmid: 20975740
references.citation: Cancer Res. 2006 Sep 15;66(18):8927-30
references.pmid: 16982728
references.citation: J Pediatr Hematol Oncol. 2010 May;32(4):339-40; author reply 340
references.pmid: 20421813
references.citation: Cancer Cell. 2010 Dec 14;18(6):553-67
references.pmid: 21130701
references.citation: Hum Mutat. 2010 Apr;31(4):380-90
references.pmid: 20052767
references.citation: Cancer Res. 2009 Dec 15;69(24):9157-9
references.pmid: 19996293
references.citation: Oncogene. 2006 Aug 7;25(34):4675-82
references.pmid: 16892081
references.citation: Pediatr Radiol. 2003 Dec;33(12):872-6
references.pmid: 12961043
references.citation: J Biol Chem. 2004 Sep 17;279(38):39968-74
references.pmid: 15254034
references.citation: Neuropathology. 2012 Feb;32(1):30-7
references.pmid: 21481010
references.citation: Ann Neurol. 2005 Oct;58(4):626-30
references.pmid: 16037974
references.citation: Cancer Res. 2010 Nov 15;70(22):8981-7
references.pmid: 21045145
references.citation: Nat Chem Biol. 2008 Mar;4(3):152-6
references.pmid: 18277970
references.citation: J Natl Cancer Inst. 2011 Jan 19;103(2):143-53
references.pmid: 21163902
references.citation: Neuropediatrics. 2008 Apr;39(2):119-22
references.pmid: 18671189