Chen Tong, Chen Huiyao, Xia Mingyang, Liao Yunfei, Li Hao, Dong Xinran, Lin Yifeng, Zhou Wenhao
Key Laboratory of Neonatal Disease, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China.
Center for Molecular Medicine, Children's Hospital of Fudan University, Shanghai, China.
NPJ Precis Oncol. 2025 Jan 10;9(1):10. doi: 10.1038/s41698-024-00792-7.
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.
髓母细胞瘤（MB）是一种侵袭性儿童脑肿瘤，具有明显的分子异质性。由于存在共同的细胞遗传学改变以及传统差异基因表达分析的局限性，在3组和4组中识别亚型特异性特征仍然具有挑战性。为了揭示潜在的分子特征和隐藏的调节因子，我们利用470例3组和4组MB患者的卡瓦利转录组图谱来重建亚型特异性调控网络。核糖体途径的强烈上调与3组中的MYC扩增有关，核磷蛋白1（NPM1）成为关键调节因子。NPM1上调定义了3组和4组中预后不良的患者亚组。抑制NPM1导致MYC扩增的3组MB细胞凋亡、c-Myc稳定性降低和翻译受损。总之，我们的研究结果突出了NPM1作为一个有前景的治疗靶点，并为MB的调控机制提供了新的见解。
