Biological and clinical significance of GSK-3beta in mantle cell lymphoma--an immunohistochemical study.

GSK-3beta, a biologically important signalling protein, is regulated by the Wnt canonical and the PI3K/Akt pathways. We recently reported that mantle cell lymphoma (MCL) frequently shows evidence of GSK-3beta inactivation, since GSK-3beta is phoshorylated at its functionally critical serine 9 residue in all MCL cell lines and the majority of MCL tumors examined. To further assess the clinical and biological significance of GSK-3beta inactivation in MCL, we employed immunohistochemistry to assess the expression of the phosphorylated/inactive form of GSK-3beta (pGSK-3beta) in 83 paraffin-embedded tumors, and correlated its expression with various biological and clinical parameters. Dichotomizing pGSK-3beta into 2 groups produced twenty-seven (32.5%) tumors assessed as negative and fifty-six (67.5%) as positive. Positive pGSK-3beta expression correlated significantly with positive nuclear expression of beta-catenin and high expression of cyclin D1 (p = 0.0025, 0.0032 Fisher's exact, respectively), both of which have been previously shown to be regulated by GSK-3beta regarding their expression levels and/or sub cellular localization in-vitro. However, no significant correlation was found between pGSK-3beta and Ki67. Of the clinical parameters, continuous pGSK-3beta status had a significant correlation with absolute lymphocyte count in blood (p = 0.0011, Spearman) and negative pGSK-3beta expression was significantly correlated with a longer overall survival (p= 0.045, HR = 1.89), but not with age at diagnosis, clinical stage or the international prognostic index. To conclude, our results support the concept that GSK-3beta inactivation, found in approximately two-thirds of MCL tumors, is biologically and clinically important in MCL.