The Wnt/β-catenin pathway plays a crucial role in the pathogenesis of various 
human cancers. In multiple myeloma (MM), aberrant auto-and/or paracrine 
activation of canonical Wnt signaling promotes proliferation and dissemination, 
while overexpression of the Wnt inhibitor Dickkopf1 (DKK1) by MM cells 
contributes to osteolytic bone disease by inhibiting osteoblast differentiation. 
Since DKK1 itself is a target of TCF/β-catenin mediated transcription, these 
findings suggest that DKK1 is part of a negative feedback loop in MM and may act 
as a tumor suppressor. In line with this hypothesis, we show here that DKK1 
expression is low or undetectable in a subset of patients with advanced MM as 
well as in MM cell lines. This absence of DKK1 is correlated with enhanced Wnt 
pathway activation, evidenced by nuclear accumulation of β-catenin, which in 
turn can be antagonized by restoring DKK1 expression. Analysis of the DKK1 
promoter revealed CpG island methylation in several MM cell lines as well as in 
MM cells from patients with advanced MM. Moreover, demethylation of the DKK1 
promoter restores DKK1 expression, which results in inhibition of 
β-catenin/TCF-mediated gene transcription in MM lines. Taken together, our data 
identify aberrant methylation of the DKK1 promoter as a cause of DKK1 silencing 
in advanced stage MM, which may play an important role in the progression of MM 
by unleashing Wnt signaling.