title: A model of a patient-derived IDH1 mutant anaplastic astrocytoma with alternative lengthening of telomeres.
abstract: Mutations in isocitrate dehydrogenase 1 (IDH1) have been found in the vast majority of low grade and progressive infiltrating gliomas and are characterized by the production of 2-hydroxyglutarate from α-ketoglutarate. Recent investigations of malignant gliomas have identified additional genetic and chromosomal abnormalities which cluster with IDH1 mutations into two distinct subgroups. The astrocytic subgroup was found to have frequent mutations in ATRX, TP53 and displays alternative lengthening of telomeres. The second subgroup with oligodendrocytic morphology has frequent mutations in CIC or FUBP1, and is linked to co-deletion of the 1p/19q arms. These mutations reflect the development of two distinct molecular pathways representing the majority of IDH1 mutant gliomas. Unfortunately, due to the scarcity of endogenously derived IDH1 mutant models, there is a lack of accurate models to study mechanism and develop new therapy. Here we report the generation of an endogenous IDH1 anaplastic astrocytoma in vivo model with concurrent mutations in TP53, CDKN2A and ATRX. The model has a similar phenotype and histopathology as the original patient tumor, expresses the IDH1 (R132H) mutant protein and exhibits an alternative lengthening of telomeres phenotype. The JHH-273 model is characteristic of anaplastic astrocytoma and represents a valuable tool for investigating the pathogenesis of this distinct molecular subset of gliomas and for preclinical testing of compounds targeting IDH1 mutations or alternative lengthening of telomeres.
authors.affiliation: Department of Neurosurgery, School of Medicine, Johns Hopkins University, 1550 Orleans Street, Room 257 CRB2, Baltimore, MD, 21231, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Borodovsky
authors.forename: Alan K
authors.initials: AK
authors.lastname: Meeker
authors.forename: Ewen F
authors.initials: EF
authors.lastname: Kirkness
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Gary L
authors.initials: GL
authors.lastname: Gallia
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
mesh_terms: D000328:Adult; D000818:Animals; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology*; D004265:DNA Helicases / Q000235:genetics; D004195:Disease Models, Animal; D019942:Genes, p16; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation / Q000379:methods; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016615:Telomere / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein