title: Mutant IDH1 Expression Drives TERT Promoter Reactivation as Part of the Cellular Transformation Process.
abstract: Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1mut) genes as they progressed through their lifespan. IDH1mutexpression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1WTor IDH1mutentered a telomere-induced crisis at PD 70. In contrast, only IDH1mutcells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo Clonal populations of postcrisis IDH1mutcells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1mutdoes not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation. Cancer Res; 76(22); 6680-9. ©2016 AACR.
authors.affiliation: Department of Neurological Surgery, Fujita Health University, Toyoake, Aichi, Japan.|Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohba
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Joydeep
authors.initials: J
authors.lastname: Mukherjee
authors.affiliation: Department of Biomedicine, The Kristian Gerhard Jebsen Brain Tumor Research Centre, University of Bergen, Bergen, Norway.
authors.forename: Tor-Christian
authors.initials: TC
authors.lastname: Johannessen
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mancini
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Chow
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wood
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Jones
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Tali
authors.initials: T
authors.lastname: Mazor
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California.
authors.forename: Roxanne E
authors.initials: RE
authors.lastname: Marshall
authors.affiliation: Department of Radiology, University of California, San Francisco, San Francisco, California.
authors.forename: Pavithra
authors.initials: P
authors.lastname: Viswanath
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.|Department of Pathology, University of California, San Francisco, San Francisco, California.
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Robert J A
authors.initials: RJ
authors.lastname: Bell
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.|Department of Pathology, University of California, San Francisco, San Francisco, California.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
authors.affiliation: Department of Radiology, University of California, San Francisco, San Francisco, California.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Ronen
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. Russ.pieper@ucsf.edu.
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
mesh_terms: D000818:Animals; D019175:DNA Methylation; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000378:metabolism*; D051379:Mice; D019098:Telomerase / Q000378:metabolism*; D014162:Transfection
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C509186:TERT protein, human; D019098:Telomerase