Increased mRNA is associated with disease relapse in favorable histology Wilms tumor (WT). This study sought to understand the mechanism of increased expression by determining the association between and WT1 and N-MYC, two proteins important in Wilms tumor pathogenesis that have been shown to regulate expression. Three out of 45 (6.7%) WTs and the corresponding patient-derived xenografts harbored canonical gain-of-function mutations in the promoter. This study identified near ubiquitous hypermethylation of the promoter region in WT compared to normal kidney. WTs with biallelic inactivating mutations in (7/45, 15.6%) were found to have lower expression by RNA-seq and qRT-PCR and lower telomerase activity determined by the telomerase repeat amplification protocol. Anaplastic histology and increased percentage of blastema were positively correlated with higher expression and telomerase activity. In vitro shRNA knockdown of resulted in decreased expression of , reduced colony formation, and decreased proliferation of WiT49, an anaplastic WT cell line with wild-type . CRISPR-Cas9-mediated knockout of resulted in decreased expression of telomere-related gene pathways. However, an inducible -knockout mouse model showed no relationship between knockout and expression in normal murine nephrogenesis, suggesting that WT1 and TERT are coupled in transformed cells but not in normal kidney tissues. N-MYC overexpression resulted in increased promoter activity and transcription. Thus, multiple mechanisms of activation are involved in WT and are associated with anaplastic histology and increased blastema. This study is novel because it identifies potential mechanisms of activation in Wilms tumor that could be of therapeutic interests.