Researchers from University of Milan, Department of Clinical Medicine publish findings in chronic myeloid leukemia

04-17-2007

A report, "Bcr-Abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylation," is newly published data in The EMBO Journal. According to a study from Monza, Italy, "Self-renewal of Bcr-Abl(+) chronic myeloid leukemia (CML) cells is sustained by a nuclear activated serine/threonine-(S/T) unphosphorylated beta-catenin. Although beta-catenin can be tyrosine (Y)-phosphorylated, the occurrence and biological relevance of this covalent modification in Bcr-Abl-associated leukemogenesis is unknown."

"Here we show that Bcr-Abl levels control the degree of beta-catenin protein stabilization by affecting its Y/S/T-phospho content in CML cells. Bcr-Abl physically interacts with beta-catenin, and its oncogenic tyrosine kinase activity is required to phosphorylate beta-catenin at Y86 and Y654 residues. This Y-phospho beta-catenin binds to the TCF4 transcription factor, thus representing a transcriptionally active pool. Imatinib, a Bcr-Abl antagonist, impairs the beta-catenin/TCF-related transcription causing a rapid cytosolic retention of Y-unphosphorylated beta-catenin, which presents an increased binding affinity for the Axin/GSK3beta complex. Although Bcr-Abl does not affect GSK3beta autophosphorylation, it prevents, through its effect on beta-catenin Y phosphorylation, Axin/GSK3beta binding to beta-catenin and its subsequent S/T phosphorylation. Silencing of beta-catenin by small interfering RNA inhibited proliferation and clonogenicity of Bcr-Abl(+) CML cells, in synergism with Imatinib," wrote A.M. Coluccia and colleagues, University of Milan, Department of Clinical Medicine.

The researchers concluded: "These findings indicate the Bcr-Abl triggered Y phosphorylation of beta-catenin as a new mechanism responsible for its protein stabilization and nuclear signalling activation in CML."

Coluccia and colleagues published the results of their research in The EMBO Journal (Bcr-Abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. The EMBO Journal, 2007;26(5):1456-66).

For additional information, contact A.M. Coluccia, University of Milano-Bicocca, Dept. of Clinical Medicine, Monza, Milan, Italy.

The publisher of the The EMBO Journal can be contacted at: Nature Publishing Group, 345 Park Avenue South, New York, NY 10010-1707, USA.

This article was prepared by Hematology Week editors from staff and other reports. Copyright 2007, Hematology Week via NewsRx.com.