title: A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT).
abstract: Glioblastoma multiforme is the most aggressive primary tumor of the central nervous system. Glioma stem cells (GSCs), a small population of tumor cells with stem-like properties, are supposedly responsible for glioblastoma multiforme relapse after current therapies. In approximately thirty percent of glioblastoma multiforme tumors, telomeres are not maintained by telomerase but through an alternative mechanism, termed alternative lengthening of telomere (ALT), suggesting potential interest in developing specific therapeutic strategies. However, no preclinical model of ALT glioma was available until the isolation of TG20 cells from a human ALT glioma. Herein, we show that TG20 cells exhibit a high level of telomeric recombination but a stable karyotype, indicating that their telomeres retain their protective function against chromosomal instability. TG20 cells possess all of the characteristic features of GSCs: the expression of neural stem cell markers, the generation of intracerebral tumors in NOD-SCID-IL2Rγ (NSG) mice as well as in nude mice, and the ability to sustain serial intracerebral transplantations without expressing telomerase, demonstrating the stability of the ALT phenotype in vivo. Furthermore, we also demonstrate that 360B, a G-quadruplex ligand of the pyridine derivative series that impairs telomere replication and mitotic progression in cancer cells, prevents the development of TG20 tumors. Together, our results show that intracerebral grafts of TG20 cells in immunodeficient mice constitute an efficient preclinical model of ALT glioblastoma multiforme and that G-quadruplex ligands are a potential therapy for this specific type of tumor.
authors.affiliation: Laboratoire de Radiopathologie, CEA, Institut de Radiobiologie Cellulaire et Moléculaire, 18 route du Panorama, 92265, Fontenay-aux-Roses, France; INSERM UMR967, 18 route du Panorama, 92265, Fontenay-aux-Roses, France; Université Paris VII, UMR967, 18 route du Panorama, 92265, Fontenay-aux-Roses, France; Université Paris XI, UMR967, 18 route du Panorama, 92265, Fontenay-aux-Roses, France.
authors.forename: Maya
authors.initials: M
authors.lastname: Jeitany
authors.forename: Jose Ramon
authors.initials: JR
authors.lastname: Pineda
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Liu
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Porreca
authors.forename: Françoise
authors.initials: F
authors.lastname: Hoffschir
authors.forename: Chantal
authors.initials: C
authors.lastname: Desmaze
authors.forename: David C
authors.initials: DC
authors.lastname: Silvestre
authors.forename: Patrick
authors.initials: P
authors.lastname: Mailliet
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Junier
authors.forename: Arturo
authors.initials: A
authors.lastname: Londoño-Vallejo
authors.forename: Evelyne
authors.initials: E
authors.lastname: Ségal-Bendirdjian
authors.forename: Hervé
authors.initials: H
authors.lastname: Chneiweiss
authors.forename: François D
authors.initials: FD
authors.lastname: Boussin
mesh_terms: D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004195:Disease Models, Animal; D054856:G-Quadruplexes; D005786:Gene Expression Regulation; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D008024:Ligands; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010641:Phenotype; D012854:Sister Chromatid Exchange; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D059505:Telomere Homeostasis
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D008024:Ligands; D019098:Telomerase
keywords: G-quadruplex ligands; alternative lengthening of telomeres; glioma stem cells; in vivo model; telomerase