Submitted February 14, 2008
Accepted July 18, 2008
Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma
Pascal Gelebart, Mona Anand, Hanan Armanious, Anthea C. Peters, Jennifer Dien Bard, Hesham M. Amin, and Raymond Lai*
Department of Laboratory Medicine & Pathology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
* Corresponding author; email: raymondmail_65{at}yahoo.com.
Aberrations of the Wnt canonical pathway (WCP) are known to contribute to the pathogenesis of various types of cancer. We hypothesize that these defects may exist in mantle cell lymphoma (MCL). Both the upstream and downstream aspects of WCP were examined in MCL cell lines and tumors. Using WCP-specific oligonucleotide arrays, we found that MCL highly and consistently expressed Wnt3 and Wnt10. 
-catenin, a transcriptional factor that is a downstream target of WCP, is localized to the nucleus and transcriptionally active in all 3 MCL cell lines examined. By immunohistochemistry, 33 of 64 (52%) MCL tumors showed nuclear localization of -catenin, which significantly correlated with the expression of the phosphorylated/inactive form of GSK3 (p-GSK3)(p=0.011, Fisher's). GSK3 inactivation is directly linked to WCP stimulation, since addition of recombinant sFRP proteins (a naturally-occurring decoy for the Wnt receptors) resulted in a significant decrease in p-GSK3. Downregulation of DvL-2 (an upstream signaling protein in WCP) by siRNA or selective inhibition of -catenin using quercetin significantly decreased cell growth in MCL cell lines. To conclude, WCP is constitutively activated in a subset of MCL and it appears to promote tumorigenesis in MCL.
