Myogenesis in Wilms' tumors is associated with mutations of the WT1 gene and activation of Bcl-2 and the Wnt signaling pathway

Pediatr Dev Pathol. Mar-Apr 2004;7(2):125-37. doi: 10.1007/s10024-003-3023-8. Epub 2004 Mar 4.


Wilms tumors with WT1 mutations [ WT1(-)] have a stromal-predominant histology with varying extents of rhabdomyogenesis. These tumors also frequently have mutations in the beta-catenin gene ( CTNNB1). We have investigated the molecular events that may explain the origins of rhabdomyogenesis in WT1(-) tumors. Of 35 Wilms tumors, we identified 12 with WT1 mutations, of which 9 carried CTNNB1 mutations. We compared WT1 wild-type tumors [ WT1(+)] with WT1(-) tumors for histological features, localization of beta-catenin, Bcl-2 expression, and apoptosis using an in-situ end-labeling technique. WT1(+) tumors showed triphasic and blastemal- and epithelial predominant-histology. Expression of WT1, beta-catenin, and Bcl-2 recapitulated those of normal kidney epithelial development. Localization of beta-catenin was observed in the cytoplasm and cytoplasmic membrane of early glomerular epithelial structures. Bcl-2 is also expressed in condensing blastema and early glomerular epithelial structures which had little apoptosis. WT1(-) tumors, regardless of whether CTNNB1 mutations were detected or not, showed a stromal-rich phenotype with abundant expression of beta-catenin in the nucleus of the rhabdomyoblasts. Bcl-2 was expressed in rhabdomyoblasts, but not in blastemal cells undergoing apoptosis, suggesting that WT1 regulates Bcl-2 positively in the epithelial pathway, but negatively in the myogenic pathway. These data indicate that mutations in WT1 might alter the Wnt signaling pathway and Bcl-2 related-apoptosis. In WT1(-) tumors, the nuclear accumulation of beta-catenin and Bcl-2 expression are associated with rhabdomyogenesis, and dysregulation of Bcl-2 may be a mechanism by which the histogenesis (loss of blastemal component, muscle differentiation) may be explained.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology
  • Cytoskeletal Proteins / metabolism
  • Gene Expression Regulation, Neoplastic / physiology
  • Genes, Wilms Tumor / physiology*
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Muscle Development / physiology*
  • Mutation
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Signal Transduction / physiology
  • Trans-Activators / metabolism
  • Wilms Tumor / genetics*
  • Wilms Tumor / metabolism
  • Wilms Tumor / pathology
  • Wnt Proteins
  • beta Catenin


  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Trans-Activators
  • Wnt Proteins
  • beta Catenin