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• W3157708001 abstract "Abstract MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. CTDNEP1 ablation transforms murine cerebellar progenitors into MYC-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes MYC protein by elevating MYC serine-62 phosphorylation, and triggers genomic instability with eventual MYC amplification and p53 loss. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for proper chromosome segregation and mitotic checkpoints including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting CHEK1 and MYC activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies identify CTDNEP1 acting as a tumor suppressor in highly aggressive medulloblastomas by maintaining homeostatic MYC levels and genomic stability, highlighting a CTDNEP1-dependent therapeutic vulnerability." @default.
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• W3157708001 date "2021-04-23" @default.
• W3157708001 modified "2023-09-27" @default.
• W3157708001 title "Loss of nuclear envelope phosphatase CTDNEP1 drives aggressive medulloblastoma by triggering MYC amplification and genomic instability" @default.
• W3157708001 doi "https://doi.org/10.21203/rs.3.rs-421098/v1" @default.
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