1. Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability.
- Author
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Luo, Zaili, Xin, Dazhuan, Liao, Yunfei, Berry, Kalen, Ogurek, Sean, Zhang, Feng, Zhang, Liguo, Zhao, Chuntao, Rao, Rohit, Dong, Xinran, Li, Hao, Yu, Jianzhong, Lin, Yifeng, Huang, Guoying, Xu, Lingli, Xin, Mei, Nishinakamura, Ryuichi, Yu, Jiyang, Kool, Marcel, Pfister, Stefan M, Roussel, Martine F, Zhou, Wenhao, Weiss, William A, Andreassen, Paul, and Lu, Q Richard
- Subjects
Animals ,Humans ,Mice ,Medulloblastoma ,Brain Neoplasms ,Cerebellar Neoplasms ,Cell Transformation ,Neoplastic ,Genomic Instability ,Phosphoric Monoester Hydrolases ,Proto-Oncogene Proteins c-myc ,Child ,Phosphoprotein Phosphatases ,Pediatric Cancer ,Genetics ,Human Genome ,Brain Cancer ,Pediatric ,Rare Diseases ,Brain Disorders ,Cancer ,Neurosciences ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,Aetiology ,5.1 Pharmaceuticals - Abstract
MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and 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 promotes the transformation of murine cerebellar progenitors into Myc-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes and activates MYC activity by elevating MYC serine-62 phosphorylation, and triggers chromosomal instability to induce p53 loss and Myc amplifications. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for chromosome segregation and mitotic checkpoint regulators including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting MYC and CHEK1 activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies demonstrate that CTDNEP1 is a tumor suppressor in highly aggressive MYC-driven medulloblastomas by controlling MYC activity and mitotic fidelity, pointing to a CTDNEP1-dependent targetable therapeutic vulnerability.
- Published
- 2023