[1465] 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.

GSK-3β and Cdc25A Expression in Lymphoma
LymphomaP-GSK-3β∗Cdc25A∗
CLL/SLL66% (50/76)96% (72/75)
MCL63% (15/24)96% (24/25)
DLBCL68% (52/76)91% (71/78)
ALCL87% (13/15)81% (13/16)
PTCL73% (22/30)79% (26/33)
HL78% (73/94)94% (100/106)
∗Percentage of neoplastic cells with moderate to strong staining


Conclusions: Our studies suggest that the GSK-3β – Cdc25A axis may contribute to the pathogenesis of a variety of lymphoma subtypes, particularly in aggressive forms such as ALCL and DLBCL. These data support further investigations of GSK-3β and Cdc25A inhibitors as potential therapies for aggressive lymphomas.
Category: Hematopathology

Monday, March 22, 2010 9:30 AM

Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 195, Monday Morning

 

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