In this study, Chen et al. provide novel insight into Wilms tumor by investigating the mechanisms by which mutations in the microRNA biogenesis machinery drive tumorigenesis. They show that the transcription factor PLAG1 is a microRNA target gene that is overexpressed in Wilms tumors with mutations in microRNA processing genes and that PLAG1 transactivates IGF2, a key Wilms tumor oncogene, and drives mTORC1 signaling.