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

Abstract

Canonical Wnt signaling regulates the transcription of T-cell factor (TCF)-responsive genes through the stabilization and nuclear translocation of the transcriptional co-activator, β-catenin. Overexpression of β-catenin features prominently in acute myeloid leukemia (AML) and has previously been associated with poor clinical outcome. Overexpression of γ-catenin mRNA (a close homologue of β-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 γ-catenin is frequent in AML. Significantly, γ-catenin expression was associated with β-catenin stabilization and nuclear localization. Consistent with this, we found that ectopic γ-catenin expression promoted the stabilization and nuclear translocation of β-catenin in leukemia cells. β-Catenin knockdown demonstrated that both γ- and β-catenin contribute to TCF-dependent transcription in leukemia cells. These data indicate that γ-catenin expression is a significant factor in the stabilization of β-catenin in AML. We also show that although normal cells exclude nuclear translocation of both γ- and β-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.

Desmosome regulation and signaling in disease

“…PG inhibits cell motility in both primary keratinocytes and prostate cancer cell lines at least in part by modulating cell-substrate adhesion dynamics in a Src-dependent and extracellular-matrix-dependent (fibronectin and vitronectin) manner (Todorović et al 2010; Franzen et al 2012). In contrast, in acute myeloid leukemia, PG has been reported to be upregulated (Morgan et al 2013). Here, PG expression promotes the stabilization beta-catenin and its nuclear translocation and enhances TCF-dependent transcription (Morgan et al 2013), all of which are associated with enhanced cell motility and tumorigenesis (Muller et al 2002).…”

“…In contrast, in acute myeloid leukemia, PG has been reported to be upregulated (Morgan et al 2013). Here, PG expression promotes the stabilization beta-catenin and its nuclear translocation and enhances TCF-dependent transcription (Morgan et al 2013), all of which are associated with enhanced cell motility and tumorigenesis (Muller et al 2002). …”

Overexpression of bone morphogenetic protein 2 through aberrant canonical Wnt/β-catenin signaling pathway plays an important role in heterotopic ossification of adrenal myelolipoma

“…Although several different pathogeneses have been postulated, 9 recent cytogenetic analyses have revealed it to be a myeloid tumour arising from misplaced hematopoietic cells. 7,10 In the present case, aberrant canonical Wnt/β-catenin signaling, typically found in variety of hematopoietic neoplasms, 11 was shown to be involved. Thus, the pathogenesis of our case appears to be compatible with the …”

Evolutionarily Conserved Signaling Pathways: Acting in the Shadows of Acute Myelogenous Leukemia's Genetic Diversity

“…In primary AML patient samples, immunohistochemical expression and constitutive activation of canonical Wnt pathway member b-catenin were also detectable in the bulk AML population (37). High expression of Ctnnb1 has been reported to correlate with poor prognosis, and g-catenin seems to stabilize the nuclear "active" version of b-catenin in AML cells (38,39). Of note, abundance of Ctnnb1 in these subentities can be considered to be a direct result of either transcriptional or posttranslational activation through the respective genetic alteration itself.…”