%0 Journal Article
%A Luo, Zaili
%A Xin, Dazhuan
%A Liao, Yunfei
%A Berry, Kalen
%A Ogurek, Sean
%A Zhang, Feng
%A Zhang, Liguo
%A Zhao, Chuntao
%A Rao, Rohit
%A Dong, Xinran
%A Li, Hao
%A Yu, Jianzhong
%A Lin, Yifeng
%A Huang, Guoying
%A Xu, Lingli
%A Xin, Mei
%A Nishinakamura, Ryuichi
%A Yu, Jiyang
%A Kool, Marcel
%A Pfister, Stefan M
%A Roussel, Martine F
%A Zhou, Wenhao
%A Weiss, William A
%A Andreassen, Paul
%A Lu, Q Richard
%T Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability.
%J Nature Communications
%V 14
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DKFZ-2023-00313
%P 762
%D 2023
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36765089
%R 10.1038/s41467-023-36400-8
%U https://inrepo02.dkfz.de/record/267535