Journal Article

DKFZ-2023-00313

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability.

Luo, Z. ; Xin, D. ; Liao, Y. ; Berry, K. ; Ogurek, S. ; Zhang, F. ; Zhang, L. ; Zhao, C. ; Rao, R. ; Dong, X. ; Li, H. ; Yu, J. ; Lin, Y. ; Huang, G. ; Xu, L. ; Xin, M. ; Nishinakamura, R. ; Yu, J. ; Kool, M.DKFZ* ; Pfister, S. M.DKFZ* ; Roussel, M. F. ; Zhou, W. ; Weiss, W. A. ; Andreassen, P. ; Lu, Q. R.

2023
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-023-36400-8

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.

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2023

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