In this study, we demonstrate MDM2 overactivity through either constitutive NF-κB activation or homozygous CDKN2A deletion as a plausible mechanism of p53 abrogation and report Actinomycin-D induced p53 reactivation at RNA, protein and functional levels in preclinical high-risk ependymoma models. This evidence concerns the gene TP53 and ependymoma.