Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma

摘要

Aberrations of the Wnt canonical pathway (WCP) are known to contribute to the patho-genesis 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. (5-catenin, a transcriptional factor that is adownstream target of WCP, is localized to the nucleus and transcriptionally active in all 3 MCL cell lines examined. By immunohis-tochemistry, 33 (52%) of 64 MCL tumors showed nuclear localization of p-catenin, which significantly correlated with the expression of the phosphorylated/inactiveform of GSK3(J (p-GSK3P; P=.O11, Fisher). GSK3p inactivation is directly linked to WCP stimulation, since addition of recombinant sFRP proteins (a naturally occurring decoyfor the Wnt receptors) resulted in a significant decrease in p-GSK3p. Down-regulation of DvL-2 (an upstream signaling protein in WCP) by siRNA or selective inhibition of (5-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.