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

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 and Q. Richard Lu ()
Additional contact information
Zaili Luo: Cincinnati Children’s Hospital Medical Center
Dazhuan Xin: Cincinnati Children’s Hospital Medical Center
Yunfei Liao: Cincinnati Children’s Hospital Medical Center
Kalen Berry: Cincinnati Children’s Hospital Medical Center
Sean Ogurek: Cincinnati Children’s Hospital Medical Center
Feng Zhang: Cincinnati Children’s Hospital Medical Center
Liguo Zhang: Cincinnati Children’s Hospital Medical Center
Chuntao Zhao: Cincinnati Children’s Hospital Medical Center
Rohit Rao: Cincinnati Children’s Hospital Medical Center
Xinran Dong: Fudan University
Hao Li: Fudan University
Jianzhong Yu: Fudan University
Yifeng Lin: Fudan University
Guoying Huang: Fudan University
Lingli Xu: Cincinnati Children’s Hospital Medical Center
Mei Xin: Cincinnati Children’s Hospital Medical Center
Ryuichi Nishinakamura: Kumamoto University
Jiyang Yu: St. Jude Children’s Research Hospital
Marcel Kool: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Stefan M. Pfister: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Martine F. Roussel: St. Jude Children’s Research Hospital
Wenhao Zhou: Fudan University
William A. Weiss: University of California San Francisco
Paul Andreassen: Cincinnati Children’s Hospital Medical Center
Q. Richard Lu: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36400-8

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