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.