C11orf95-RELA fusions drive oncogenic NF-
Menée sur des échantillons tumoraux prélevés sur des patients atteints de divers types d'épendymomes, puis à l'aide de modèles murins, cette étude identifie de fréquentes mutations du gène RELA et, pour les tumeurs sus-tentorielles, met en évidence des mécanismes par lesquels, via la régulation de la signalisation
Members of the nuclear factor-
κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95
–RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95–RELA fusion proteins translocated spontaneously to the nucleus to activate NF-
κB target genes, and rapidly transformed neural stem cells
—the cell of origin of ependymoma—to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95–RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.