MDB-02. NUCLEAR ENVELOPE PHOSPHATASE CTDNEP1 MUTATIONS POTENTIATE AGGRESSIVE MEDULLOBLASTOMA BY TRIGGERING MYC ACTIVATION AND GENOMIC INSTABILITY

Abstract MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and genetic events triggering MYC amplification malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, most significantly enriched recurrent alterations medulloblastomas, define high-risk subsets with poorer prognosis. Ctdnep1 ablation promotes of murine cerebellar progenitors into Myc-amplified resembling their human counterparts. CTDNEP1 deficiency stabilizes activates activity by elevating serine-62 phosphorylation, triggers chromosomal instability to induce p53 loss Myc amplifications. Further, phosphoproteomics reveals post-translationally modulates activities key regulators for chromosome segregation mitotic checkpoint including topoisomerase TOP2A kinase CHEK1. Co-targeting CHEK1 synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth prolongs animal survival. Together, our studies demonstrate is potent suppressor controlling fidelity, pointing CTDNEP1-dependent targetable therapeutic vulnerability.