Substantial evidence links Myc-PI3K/AKT signalling to the most aggressive subtype of medulloblastoma (MB) and this axis in MB therapy. In this study, we advance understanding of how Myc-PI3K/AKT signalling contributes to this malignancy, specifically, in identifying the Myc-interacting protein JPO2 and its partner binding protein LEDGF/p75 as critical modulators of PI3K/AKT signalling and metastasis in MB. JPO2 overexpression induced metastatic MB in vivo through two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT that promote metastatic phenotypes in this settng. Overall, our findings highlight two novel pro-metastatic loci in MB and point to the JPO2:LEDGF/p75 protein complex as a potentially new targetable component of P13K/AKT signalling in MB.
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