Evaluation of Functional GSK-3β-Cdc25A Axis in Hodgkin and Non-Hodgkin Lymphomas
E Wey, C Mankey, S McDonnell, A Kronk, D Thomas, F Keyoumarsi, K Elenitoba-Johnson, M Lim. University of Michigan, Ann Arbor, MI
Background: Cdc25A is an oncogene that is overexpressed in many human cancers and is a key regulator of the G1/S transition. Glycogen synthase kinase-3β (GSK-3β) targets Cdc25A for degradation and inactive (phosphorylated) GSK-3β correlated with Cdc25A expression. Cdc25A mRNA is associated with histologic and clinical aggressiveness in non-Hodgkin lymphomas but no studies exist evaluating Cdc25A protein expression in a large panel of lymphomas. Furthermore, our in vitro chemical screen of compounds that target kinases identified GSK-3β inhibitors as having a negative effect on the growth of a variety of lymphoma-derived cell lines. In this study, we evaluated the expression of Cdc25A, GSK-3β and its phosphorylated form p-GSK-3β (inactive), in a large panel of lymphomas (n=334).
Design: Tissue microarrays were constructed using material available at the University of Michigan. Diagnoses included chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), peripheral T cell lymphoma (PTCL) and Hodgkin lymphoma (HL). Immunohistochemistry was performed with specific antibodies to GSK-3β, p-GSK-3β and Cdc25A and evaluated using parameters of staining intensity, percentage of immunoreactive neoplastic cells and cytoplasmic versus nuclear staining. Reactive tonsils were used as control tissues.
Results: The expression of p-GSK-3β was cytoplasmic while Cdc25A expression was nuclear. P-GSK-3β and Cdc25A were expressed in all lymphoma types with moderate to strong intensity (see Table). Furthermore, a positive correlation between p-GSK-3β and Cdc25A was observed in almost all lymphoma subsets with relatively strong correlation in DLBCL (r2=0.48) and in ALCL (r2=0.65), independent of ALK status. A negative correlation was observed in neoplastic cells of HL.
|CLL/SLL||66% (50/76)||96% (72/75)|
|MCL||63% (15/24)||96% (24/25)|
|DLBCL||68% (52/76)||91% (71/78)|
|ALCL||87% (13/15)||81% (13/16)|
|PTCL||73% (22/30)||79% (26/33)|
|HL||78% (73/94)||94% (100/106)|