γ-Catenin is overexpressed in acute myeloid leukemia and promotes the stabilization and nuclear localization of β-catenin

Canonical Wnt signaling regulates the transcription of T-cell factor (TCF)-responsive genes through the stabilization and nuclear translocation of the transcriptional co-activator, beta-catenin. Overexpression of beta-catenin features prominently in acute myeloid leukemia (AML) and has previously been associated with poor clinical outcome. Overexpression of gamma-catenin mRNA (a close homologue of beta-catenin) has also been reported in AML and has been linked to the pathogenesis of this disease, however, the relative roles of these catenins in leukemia remains unclear. Here we report that overexpression and aberrant nuclear localization of gamma-catenin is frequent in AML. Significantly, gamma-catenin expression was associated with beta-catenin stabilization and nuclear localization. Consistent with this, we found that ectopic gamma-catenin expression promoted the stabilization and nuclear translocation of beta-catenin in leukemia cells. beta-Catenin knockdown demonstrated that both gamma- and beta-catenin contribute to TCF-dependent transcription in leukemia cells. These data indicate that gamma-catenin expression is a significant factor in the stabilization of beta-catenin in AML. We also show that although normal cells exclude nuclear translocation of both gamma- and beta-catenin, this level of regulation is lost in the majority of AML patients and cell lines, which allow nuclear accumulation of these catenins and inappropriate TCF-dependent transcription. Leukemia (2013) 27, 336-343; doi:10.1038/leu.2012.221