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| Home > Publications database > Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability. > print |
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| 100 | 1 | _ | |a Luo, Zaili |0 0000-0002-8773-604X |b 0 |
| 245 | _ | _ | |a Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability. |
| 260 | _ | _ | |a [London] |c 2023 |b Nature Publishing Group UK |
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| 520 | _ | _ | |a 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. |
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| 700 | 1 | _ | |a Xin, Dazhuan |b 1 |
| 700 | 1 | _ | |a Liao, Yunfei |b 2 |
| 700 | 1 | _ | |a Berry, Kalen |b 3 |
| 700 | 1 | _ | |a Ogurek, Sean |b 4 |
| 700 | 1 | _ | |a Zhang, Feng |b 5 |
| 700 | 1 | _ | |a Zhang, Liguo |b 6 |
| 700 | 1 | _ | |a Zhao, Chuntao |b 7 |
| 700 | 1 | _ | |a Rao, Rohit |b 8 |
| 700 | 1 | _ | |a Dong, Xinran |0 0000-0001-9868-8795 |b 9 |
| 700 | 1 | _ | |a Li, Hao |b 10 |
| 700 | 1 | _ | |a Yu, Jianzhong |b 11 |
| 700 | 1 | _ | |a Lin, Yifeng |b 12 |
| 700 | 1 | _ | |a Huang, Guoying |b 13 |
| 700 | 1 | _ | |a Xu, Lingli |b 14 |
| 700 | 1 | _ | |a Xin, Mei |0 0000-0002-5732-7501 |b 15 |
| 700 | 1 | _ | |a Nishinakamura, Ryuichi |b 16 |
| 700 | 1 | _ | |a Yu, Jiyang |0 0000-0003-3629-4330 |b 17 |
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| 700 | 1 | _ | |a Roussel, Martine F |0 0000-0002-1740-8139 |b 20 |
| 700 | 1 | _ | |a Zhou, Wenhao |0 0000-0001-8956-7238 |b 21 |
| 700 | 1 | _ | |a Weiss, William A |b 22 |
| 700 | 1 | _ | |a Andreassen, Paul |0 0000-0002-9760-1595 |b 23 |
| 700 | 1 | _ | |a Lu, Q Richard |0 0000-0001-6846-9014 |b 24 |
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