Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability
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 enric...
Gespeichert in:
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
10 February 2023
|
| In: |
Nature Communications
Year: 2023, Jahrgang: 14, Pages: 1-19 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-023-36400-8 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-023-36400-8 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-023-36400-8 
|
| Verfasserangaben: | 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 & Q. Richard Lu |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1862649960 | ||
| 003 | DE-627 | ||
| 005 | 20240307050713.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231012s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41467-023-36400-8 |2 doi | |
| 035 | |a (DE-627)1862649960 | ||
| 035 | |a (DE-599)KXP1862649960 | ||
| 035 | |a (OCoLC)1425210562 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Luo, Zaili |e VerfasserIn |0 (DE-588)1311581820 |0 (DE-627)1871575966 |4 aut | |
| 245 | 1 | 0 | |a Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability |c 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 & Q. Richard Lu |
| 264 | 1 | |c 10 February 2023 | |
| 300 | |b Illustrationen | ||
| 300 | |a 19 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 29.11.2023 | ||
| 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. | ||
| 650 | 4 | |a Cancer genomics | |
| 650 | 4 | |a CNS cancer | |
| 650 | 4 | |a Tumour-suppressor proteins | |
| 700 | 1 | |a Xin, Dazhuan |e VerfasserIn |4 aut | |
| 700 | 1 | |a Liao, Yunfei |e VerfasserIn |4 aut | |
| 700 | 1 | |a Berry, Kalen |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ogurek, Sean |e VerfasserIn |4 aut | |
| 700 | 1 | |a Zhang, Feng |e VerfasserIn |4 aut | |
| 700 | 1 | |a Zhang, Liguo |e VerfasserIn |4 aut | |
| 700 | 1 | |a Zhao, Chuntao |e VerfasserIn |4 aut | |
| 700 | 1 | |a Rao, Rohit |e VerfasserIn |4 aut | |
| 700 | 1 | |a Dong, Xinran |e VerfasserIn |4 aut | |
| 700 | 1 | |a Li, Hao |e VerfasserIn |4 aut | |
| 700 | 1 | |a Yu, Jianzhong |e VerfasserIn |4 aut | |
| 700 | 1 | |a Lin, Yifeng |e VerfasserIn |4 aut | |
| 700 | 1 | |a Huang, Guoying |e VerfasserIn |4 aut | |
| 700 | 1 | |a Xu, Lingli |e VerfasserIn |4 aut | |
| 700 | 1 | |a Xin, Mei |e VerfasserIn |4 aut | |
| 700 | 1 | |a Nishinakamura, Ryuichi |e VerfasserIn |4 aut | |
| 700 | 1 | |a Yu, Jiyang |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kool, Marcel |e VerfasserIn |0 (DE-588)1058669753 |0 (DE-627)797393560 |0 (DE-576)414823842 |4 aut | |
| 700 | 1 | |a Pfister, Stefan |d 1974- |e VerfasserIn |0 (DE-588)123850215 |0 (DE-627)706450930 |0 (DE-576)293908400 |4 aut | |
| 700 | 1 | |a Roussel, Martine F. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Zhou, Wenhao |e VerfasserIn |4 aut | |
| 700 | 1 | |a Weiss, William A. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Andreassen, Paul |e VerfasserIn |4 aut | |
| 700 | 1 | |a Lu, Q. Richard |e VerfasserIn |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature Communications |d [London] : Springer Nature, 2010 |g 14(2023), Artikel-ID 762, Seite 1-19 |h Online-Ressource |w (DE-627)626457688 |w (DE-600)2553671-0 |w (DE-576)331555905 |x 2041-1723 |7 nnas |a Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability |
| 773 | 1 | 8 | |g volume:14 |g year:2023 |g elocationid:762 |g pages:1-19 |g extent:19 |a Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability |
| 856 | 4 | 0 | |u https://doi.org/10.1038/s41467-023-36400-8 |x Verlag |x Resolving-System |z kostenfrei |3 Volltext |
| 856 | 4 | 0 | |u https://www.nature.com/articles/s41467-023-36400-8 |x Verlag |z kostenfrei |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20231012 | ||
| 993 | |a Article | ||
| 994 | |a 2023 | ||
| 998 | |g 123850215 |a Pfister, Stefan |m 123850215:Pfister, Stefan |d 910000 |d 910500 |e 910000PP123850215 |e 910500PP123850215 |k 0/910000/ |k 1/910000/910500/ |p 20 | ||
| 998 | |g 1058669753 |a Kool, Marcel |m 1058669753:Kool, Marcel |d 50000 |e 50000PK1058669753 |k 0/50000/ |p 19 | ||
| 999 | |a KXP-PPN1862649960 |e 4385609241 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"person":[{"display":"Luo, Zaili","family":"Luo","role":"aut","given":"Zaili"},{"display":"Xin, Dazhuan","family":"Xin","role":"aut","given":"Dazhuan"},{"display":"Liao, Yunfei","family":"Liao","role":"aut","given":"Yunfei"},{"given":"Kalen","display":"Berry, Kalen","role":"aut","family":"Berry"},{"display":"Ogurek, Sean","family":"Ogurek","role":"aut","given":"Sean"},{"display":"Zhang, Feng","role":"aut","family":"Zhang","given":"Feng"},{"role":"aut","family":"Zhang","display":"Zhang, Liguo","given":"Liguo"},{"display":"Zhao, Chuntao","family":"Zhao","role":"aut","given":"Chuntao"},{"given":"Rohit","role":"aut","family":"Rao","display":"Rao, Rohit"},{"family":"Dong","role":"aut","display":"Dong, Xinran","given":"Xinran"},{"given":"Hao","role":"aut","family":"Li","display":"Li, Hao"},{"given":"Jianzhong","role":"aut","family":"Yu","display":"Yu, Jianzhong"},{"family":"Lin","role":"aut","display":"Lin, Yifeng","given":"Yifeng"},{"given":"Guoying","family":"Huang","role":"aut","display":"Huang, Guoying"},{"given":"Lingli","family":"Xu","role":"aut","display":"Xu, Lingli"},{"given":"Mei","display":"Xin, Mei","role":"aut","family":"Xin"},{"given":"Ryuichi","family":"Nishinakamura","role":"aut","display":"Nishinakamura, Ryuichi"},{"display":"Yu, Jiyang","role":"aut","family":"Yu","given":"Jiyang"},{"display":"Kool, Marcel","family":"Kool","role":"aut","given":"Marcel"},{"display":"Pfister, Stefan","family":"Pfister","role":"aut","given":"Stefan"},{"given":"Martine F.","display":"Roussel, Martine F.","role":"aut","family":"Roussel"},{"given":"Wenhao","display":"Zhou, Wenhao","role":"aut","family":"Zhou"},{"family":"Weiss","role":"aut","display":"Weiss, William A.","given":"William A."},{"given":"Paul","family":"Andreassen","role":"aut","display":"Andreassen, Paul"},{"given":"Q. Richard","display":"Lu, Q. Richard","family":"Lu","role":"aut"}],"language":["eng"],"note":["Gesehen am 29.11.2023"],"name":{"displayForm":["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 & Q. Richard Lu"]},"origin":[{"dateIssuedDisp":"10 February 2023","dateIssuedKey":"2023"}],"type":{"bibl":"article-journal","media":"Online-Ressource"},"recId":"1862649960","id":{"doi":["10.1038/s41467-023-36400-8"],"eki":["1862649960"]},"title":[{"title_sort":"Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability","title":"Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability"}],"physDesc":[{"noteIll":"Illustrationen","extent":"19 S."}],"relHost":[{"disp":"Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instabilityNature Communications","origin":[{"publisher":"Springer Nature ; Nature Publishing Group UK","publisherPlace":"[London] ; [London]","dateIssuedDisp":"[2010]-"}],"id":{"issn":["2041-1723"],"zdb":["2553671-0"],"eki":["626457688"]},"recId":"626457688","type":{"media":"Online-Ressource","bibl":"periodical"},"note":["Gesehen am 13.06.24"],"pubHistory":["2010-"],"language":["eng"],"part":{"extent":"19","volume":"14","text":"14(2023), Artikel-ID 762, Seite 1-19","pages":"1-19","year":"2023"},"physDesc":[{"extent":"Online-Ressource"}],"title":[{"title":"Nature Communications","title_sort":"Nature Communications"}]}]} | ||
| SRT | |a LUOZAILIXILOSSOFPHOS1020 | ||