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Many childhood Wilms tumors are driven by mutations in the microRNA biogenesis machinery, but the mechanism by which these mutations drive tumorigenesis is unknown. Here we show that the transcription factor  pleomorphic adenoma gene 1 (PLAG1 ) is a microRNA target gene that is overexpressed in Wilms tumors with mutations in microRNA processing genes. Wilms tumors can also overexpress  PLAG1  through copy number alterations, and  PLAG1  expression correlates with prognosis in Wilms tumors.  PLAG1  overexpression accelerates growth of Wilms tumor cells in vitro and induces neoplastic growth in the developing mouse kidney in vivo. In both settings,  PLAG1  transactivates  insulin-like growth factor 2  ( IGF2 ), a key Wilms tumor oncogene, and drives mammalian target of rapamycin complex 1 (mTORC1) signaling. These data link microRNA impairment to the PLAG1–IGF2 pathway, providing new insight into the manner in which common Wilms tumor mutations drive disease pathogenesis.

Mutations in microRNA processing genes in Wilms tumors derepress the IGF2 regulator PLAG1