ABSTRACT We have identified mutations in the X-linked, RNA helicase DDX3X as the second most frequent mutation in medulloblastoma (MB). We now show that DDX3X: (i) orchestrates normal hindbrain patterning and development; (ii) suppresses the initiation of Wnt and Shh MB; (iii) restricts the susceptibility of specific NPCs to generate these tumors; and (iv) serves as a `rheostat' in the stress response, regulating global patterns of gene transcription and translation and live-die `decisions. Our studies also helped explain why WNT-MBs are eminently curable. We showed that paracrine signals driven by mutant CTNNB1 in WNT-MB disrupts the blood brain barrier (BBB), permitting the accumulation of high levels of intra-tumoral chemotherapy and a robust therapeutic response. Here, we will continue our focus on WNT-MB to address three new Specific Aims that will: determine how DDX3X regulates cell fate decisions in the normal and malignant hindbrain; generate novel immunotherapies of WNT MB; and translate new treatments of WNT MB to clinical trial.