In-depth inference of transcriptional regulatory networks reveals NPM1 as a therapeutic ribosomal regulator in MYC-amplified medulloblastoma
Abstract Medulloblastoma (MB) is an aggressive pediatric brain tumor with distinct molecular heterogeneity. Identifying subtype-specific signatures within Group 3 and Group 4 remains challenging due to shared cytogenetic alterations and limitations of conventional differential gene expression analys...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-024-00792-7 |
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| author | Tong Chen Huiyao Chen Mingyang Xia Yunfei Liao Hao Li Xinran Dong Yifeng Lin Wenhao Zhou |
| author_facet | Tong Chen Huiyao Chen Mingyang Xia Yunfei Liao Hao Li Xinran Dong Yifeng Lin Wenhao Zhou |
| author_sort | Tong Chen |
| collection | DOAJ |
| description | Abstract Medulloblastoma (MB) is an aggressive pediatric brain tumor with distinct molecular heterogeneity. Identifying subtype-specific signatures within Group 3 and Group 4 remains challenging due to shared cytogenetic alterations and limitations of conventional differential gene expression analysis. To uncover the underlying molecular signatures and hidden regulators, we used the Cavalli transcriptomic profile of 470 Group 3 and Group 4 MB patients to reconstruct subtype-specific regulatory networks. A strong upregulation of the ribosomal pathway was linked to MYC amplification in Group 3, with Nucleophosmin 1 (NPM1) emerging as a key regulator. NPM1 upregulation defined a subset of Group3 and Group4 patients with poor prognosis. Inhibition of NPM1 led to apoptosis, reduced c-Myc stability, and impaired translation in MYC-amplified Group 3 MB cells. Together, our findings highlight NPM1 as a promising therapeutic target and provide new insights into the regulatory mechanisms in MB. |
| format | Article |
| id | doaj-art-fb967bdfa8c9443c842ea5ac112d7cb2 |
| institution | DOAJ |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-fb967bdfa8c9443c842ea5ac112d7cb22025-08-20T02:40:27ZengNature Portfolionpj Precision Oncology2397-768X2025-01-019111310.1038/s41698-024-00792-7In-depth inference of transcriptional regulatory networks reveals NPM1 as a therapeutic ribosomal regulator in MYC-amplified medulloblastomaTong Chen0Huiyao Chen1Mingyang Xia2Yunfei Liao3Hao Li4Xinran Dong5Yifeng Lin6Wenhao Zhou7Key Laboratory of Neonatal Disease, Ministry of Health, Children’s Hospital of Fudan UniversityCenter for Molecular Medicine, Children’s Hospital of Fudan UniversityKey Laboratory of Birth Defects, Children’s Hospital of Fudan University, Fudan UniversityCenter for Molecular Medicine, Children’s Hospital of Fudan UniversityDepartment of Neurosurgery, Children’s Hospital of Fudan UniversityCenter for Molecular Medicine, Children’s Hospital of Fudan UniversityKey Laboratory of Neonatal Disease, Ministry of Health, Children’s Hospital of Fudan UniversityDivision of Neonatology and Center for Newborn Care, Guangzhou Women and Children’s Medical Center, Guangzhou Medical UniversityAbstract Medulloblastoma (MB) is an aggressive pediatric brain tumor with distinct molecular heterogeneity. Identifying subtype-specific signatures within Group 3 and Group 4 remains challenging due to shared cytogenetic alterations and limitations of conventional differential gene expression analysis. To uncover the underlying molecular signatures and hidden regulators, we used the Cavalli transcriptomic profile of 470 Group 3 and Group 4 MB patients to reconstruct subtype-specific regulatory networks. A strong upregulation of the ribosomal pathway was linked to MYC amplification in Group 3, with Nucleophosmin 1 (NPM1) emerging as a key regulator. NPM1 upregulation defined a subset of Group3 and Group4 patients with poor prognosis. Inhibition of NPM1 led to apoptosis, reduced c-Myc stability, and impaired translation in MYC-amplified Group 3 MB cells. Together, our findings highlight NPM1 as a promising therapeutic target and provide new insights into the regulatory mechanisms in MB.https://doi.org/10.1038/s41698-024-00792-7 |
| spellingShingle | Tong Chen Huiyao Chen Mingyang Xia Yunfei Liao Hao Li Xinran Dong Yifeng Lin Wenhao Zhou In-depth inference of transcriptional regulatory networks reveals NPM1 as a therapeutic ribosomal regulator in MYC-amplified medulloblastoma npj Precision Oncology |
| title | In-depth inference of transcriptional regulatory networks reveals NPM1 as a therapeutic ribosomal regulator in MYC-amplified medulloblastoma |
| title_full | In-depth inference of transcriptional regulatory networks reveals NPM1 as a therapeutic ribosomal regulator in MYC-amplified medulloblastoma |
| title_fullStr | In-depth inference of transcriptional regulatory networks reveals NPM1 as a therapeutic ribosomal regulator in MYC-amplified medulloblastoma |
| title_full_unstemmed | In-depth inference of transcriptional regulatory networks reveals NPM1 as a therapeutic ribosomal regulator in MYC-amplified medulloblastoma |
| title_short | In-depth inference of transcriptional regulatory networks reveals NPM1 as a therapeutic ribosomal regulator in MYC-amplified medulloblastoma |
| title_sort | in depth inference of transcriptional regulatory networks reveals npm1 as a therapeutic ribosomal regulator in myc amplified medulloblastoma |
| url | https://doi.org/10.1038/s41698-024-00792-7 |
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