TY  - JOUR
AU  - Luo, Zaili
AU  - Xin, Dazhuan
AU  - Liao, Yunfei
AU  - Berry, Kalen
AU  - Ogurek, Sean
AU  - Zhang, Feng
AU  - Zhang, Liguo
AU  - Zhao, Chuntao
AU  - Rao, Rohit
AU  - Dong, Xinran
AU  - Li, Hao
AU  - Yu, Jianzhong
AU  - Lin, Yifeng
AU  - Huang, Guoying
AU  - Xu, Lingli
AU  - Xin, Mei
AU  - Nishinakamura, Ryuichi
AU  - Yu, Jiyang
AU  - Kool, Marcel
AU  - Pfister, Stefan M
AU  - Roussel, Martine F
AU  - Zhou, Wenhao
AU  - Weiss, William A
AU  - Andreassen, Paul
AU  - Lu, Q Richard
TI  - Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability.
JO  - Nature Communications
VL  - 14
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2023-00313
SP  - 762
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36765089
DO  - DOI:10.1038/s41467-023-36400-8
UR  - https://inrepo02.dkfz.de/record/267535
ER  -