MEDU-44. MUSASHI-1 IS A MASTER REGULATOR OF ABERRANT TRANSLATION IN GROUP 3 MEDULLOBLASTOMA

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with group 3 (G3) MB representing the poorest prognostic subgroup with a remarkable ability to resist upfront multimodal therapy. Despite a low mutational burden of disease and MYC amplification identified as a independent factor associated with poor survivorship, efforts to target MYC or the MYC-MAX complex has met with limited therapeutic success. Consequently alternative mediators associated with the aggressive phenotype of G3 MB continues as a common goal within the MB community. Here we show how the neural stem cell determinant Musashi 1 (MSI1) is a central and vital moderator of G3 MB. Specifically, we employed shRNA inhibition against Msi1 in multiple patient derived cell lines, observing a striking deficit in multiple key stem cell features. Notably, in our MYC amplified G3 MB patient derived xenograft (PDX) models, Msi1 inhibition resulted in a failure of tumor initiation, translating to a significantly prolonged survival, reaffirming the essential role for MSI1 in G3 MB. To determine how MSI1 symphonizes the anarchic post-transcriptional landscape of G3 MB, an unbiased approach using enhanced cross-linking and immunoprecipitation (eCLIP) of both normal neural stem cells and G3 MB provided insight into the aberrant function of MSI1 in G3 MB. To further tease out the functional mechanism of MSI1, a multi-platform study of the 1) eCLIP binding targets, and differential analysis post-Msi1 inhibition at the 2) transcriptome-, and 3) proteome-wide scale was completed to inform targeted drug discovery. MSI1 not only binds and moderates MYC and OTatrt-14 X2 but other key G3 MB associated gene transcripts. Here we propose the neural RNA binding protein MSI1, as a master regulator, hijacked from its normal neural developmental function, orchestrating the aberrant translational landscape of G3 MB.