Blockade of JAK2 Activity Suppressed Accumulation of β-Catenin in Leukemic Cells

The Wnt/beta-catenin pathway has been implicated in leukemogenesis. We found beta-catenin abnormally accumulated in both human acute T cell leukemia Jurkat cells and human erythroleukemia HEL cells. beta-Catenin can be significantly down-regulated by the Janus kinase 2 specific inhibitor AG490 in these two cells. AG490 also reduces the luciferase activity of a reporter plasmid driven by LEF/beta-catenin promoter. Similar results were observed in HEL cells infected with lentivirus containing shRNA against JAK2 gene. After treatment with 50 mu M AG490 or shRNA, the mRNA expression levels of beta-catenin, APC, Axin, beta-Trcp, GSK3 alpha, and GSK3 beta were up-regulated within 12-16 h. However, only the protein levels of GSK3 beta and beta-Trcp were found to have increased relative to untreated cells. Knockdown experiments revealed that the AG490-induced inhibition of beta-catenin can be attenuated by shRNA targeting beta-TrCP. Taken together; these results suggest that beta-Trcp plays a key role in the cross-talk between JAK/STAT and Wnt/beta-catenin signaling in leukemia cells. J. Cell. Biochem. 111: 402-411, 2010. (C) 2010 Wiley-Liss, Inc.