Characterization of D-Cyclin Proteins in Hematolymphoid Neoplasms: Lack of Specificity of Cyclins D2 and D3 Expression in Lymphoma Subtypes

D-cyclin proteins play a central role in cell cycle regulation and are involved in the pathogenesis of lymphomas. In mantle cell lymphoma, the t(11;14) translocation leads to the overexpression of cyclin D1, in addition to which cyclin D1-negative mantle cell lymphoma that overexpress cyclin D2 or D3 have also been described. Although cyclins D2 and D3 have been implicated in the prognosis of specific lymphoma subtypes, a thorough characterization of D-cyclin protein expression in human hematolymphoid neoplasia has not been reported. To evaluate the tissue expression patterns of D-cyclins, particularly D2 and D3, in normal and neoplastic hematolymphoid tissues, we optimized commercially available antibodies for D-cyclins for use on paraffin-embedded tissue and stained tissue microarrays of over 700 patient samples. Our results show that cyclin D2 and D3 proteins are expressed in many more lymphoma subtypes than cyclin D1. Cyclins D1, D2 and D3 were expressed in 100%, 22% and 6% of mantle cell lymphoma and 2%, 49% and 20% of diffuse large B-cell lymphoma. Fluorescence in situ hybridization studies confirmed the presence of the CCND1/IGH translocation in the majority of mantle cell lymphoma but not in diffuse large B-cell lymphoma that expressed cyclin D1 protein. In addition, a subset of follicular, marginal zone, lymphoplasmacytic, lymphoblastic, classical Hodgkin, mature T- and Natural Killer cell lymphomas and acute myeloid leukemias also expressed cyclins D2 and D3. These data support the hypothesis that dysregulation of cell cycle control by D-cyclins contribute to the pathogenesis of hematolymphoid neoplasia, and suggest a potential role for these proteins in the prognostic and therapeutic aspects of these diseases. For diagnostic purposes, however, the expression of D-cyclin proteins should be interpreted with caution in the subclassification of lymphoma types.