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Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability

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 enric...

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Main Authors: Luo, Zaili (Author) , Xin, Dazhuan (Author) , Liao, Yunfei (Author) , Berry, Kalen (Author) , Ogurek, Sean (Author) , Zhang, Feng (Author) , Zhang, Liguo (Author) , Zhao, Chuntao (Author) , Rao, Rohit (Author) , Dong, Xinran (Author) , Li, Hao (Author) , Yu, Jianzhong (Author) , Lin, Yifeng (Author) , Huang, Guoying (Author) , Xu, Lingli (Author) , Xin, Mei (Author) , Nishinakamura, Ryuichi (Author) , Yu, Jiyang (Author) , Kool, Marcel (Author) , Pfister, Stefan (Author) , Roussel, Martine F. (Author) , Zhou, Wenhao (Author) , Weiss, William A. (Author) , Andreassen, Paul (Author) , Lu, Q. Richard (Author)
Format: Article (Journal)
Language:English
Published: 10 February 2023
In: Nature Communications
Year: 2023, Volume: 14, Pages: 1-19
ISSN:2041-1723
DOI:10.1038/s41467-023-36400-8
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-023-36400-8
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-023-36400-8
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Author Notes:Zaili Luo, Dazhuan Xin, Yunfei Liao, Kalen Berry, Sean Ogurek, Feng Zhang, Liguo Zhang, Chuntao Zhao, Rohit Rao, Xinran Dong, Hao Li, Jianzhong Yu, Yifeng Lin, Guoying Huang, Lingli Xu, Mei Xin, Ryuichi Nishinakamura, Jiyang Yu, Marcel Kool, Stefan M. Pfister, Martine F. Roussel, Wenhao Zhou, William A. Weiss, Paul Andreassen & Q. Richard Lu
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Summary: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.
Item Description:Gesehen am 29.11.2023
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-023-36400-8

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