A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT)

Glioblastomamultiforme 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 glioblastomamultiforme relapse after current therapies. In approximately thirty percent of glioblastomamultiforme tumors, telomeresare 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 telomericrecombination but a stable karyotype, indicating that their telomeresretain their protective function against chromosomal instability. TG20 cells possess all of the characteristic features of GSCs: the expression of neural stem cellmarkers, the generation of intrace-rebral tumors in NOD-SCID-IL2Rc (NSG) mice as well as in nude mice, and the ability to sustain serial intracerebral transplan-tations without expressing telomerase, demonstrating the stability of the ALT phenotype in vivo. Furthermore, we also demonstrate that 360B, a G-quadruplexligand of the pyridine derivative series that impairs telomerereplication 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 glioblastomamultiforme and that G-quadruplexligands are a potential therapy for this specific type of tumor.