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000267535 1001_ $$00000-0002-8773-604X$$aLuo, Zaili$$b0
000267535 245__ $$aLoss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability.
000267535 260__ $$a[London]$$bNature Publishing Group UK$$c2023
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000267535 520__ $$aMYC-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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000267535 7001_ $$aXin, Dazhuan$$b1
000267535 7001_ $$aLiao, Yunfei$$b2
000267535 7001_ $$aBerry, Kalen$$b3
000267535 7001_ $$aOgurek, Sean$$b4
000267535 7001_ $$aZhang, Feng$$b5
000267535 7001_ $$aZhang, Liguo$$b6
000267535 7001_ $$aZhao, Chuntao$$b7
000267535 7001_ $$aRao, Rohit$$b8
000267535 7001_ $$00000-0001-9868-8795$$aDong, Xinran$$b9
000267535 7001_ $$aLi, Hao$$b10
000267535 7001_ $$aYu, Jianzhong$$b11
000267535 7001_ $$aLin, Yifeng$$b12
000267535 7001_ $$aHuang, Guoying$$b13
000267535 7001_ $$aXu, Lingli$$b14
000267535 7001_ $$00000-0002-5732-7501$$aXin, Mei$$b15
000267535 7001_ $$aNishinakamura, Ryuichi$$b16
000267535 7001_ $$00000-0003-3629-4330$$aYu, Jiyang$$b17
000267535 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b18$$udkfz
000267535 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b19$$udkfz
000267535 7001_ $$00000-0002-1740-8139$$aRoussel, Martine F$$b20
000267535 7001_ $$00000-0001-8956-7238$$aZhou, Wenhao$$b21
000267535 7001_ $$aWeiss, William A$$b22
000267535 7001_ $$00000-0002-9760-1595$$aAndreassen, Paul$$b23
000267535 7001_ $$00000-0001-6846-9014$$aLu, Q Richard$$b24
000267535 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-023-36400-8$$gVol. 14, no. 1, p. 762$$n1$$p762$$tNature Communications$$v14$$x2041-1723$$y2023
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