Characterization of D-cyclin proteins in hematolymphoid neoplasms: lack of specificity of cyclin-D2 and D3 expression in lymphoma subtypes

Abstract

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.

Cyclin D3 coordinates the cell cycle during differentiation to regulate erythrocyte size and number

“…4). We noticed that cyclin D3 was well expressed in early erythroid progenitors, with maximal expression in cells at the proerythroblast stage of differentiation, and underwent a decrease in expression as the cells underwent subsequent terminal differentiation, consistent with findings from prior studies (Dai et al 2000;Metcalf et al 2010). The decrease in cyclin D3 expression occurred concomitantly with the period when cell cycle exit occurs during terminal erythropoiesis, suggesting a potential role for this protein in the regulation of this process.…”

“…5B). This finding is consistent with the patterns of expression seen for these different D cyclins, with cyclin D3 being the predominant protein in terminal erythroid precursor cells (Ciemerych et al 2002;Metcalf et al 2010). When the bone marrow in adult mice was examined before and after stimulation with Epo, no major difference among progenitors at various stages of differentiation was noted (Supplemental Fig.…”

“…Among the D cyclins, cyclin D3 is one of the least well studied. It has been suggested to have a role in certain cancers, particularly those of hematopoietic origin (Sicinska et al 2003;Metcalf et al 2010). Indeed, rearrangements involving the CCND3 gene have been seen in cases of multiple myeloma and diffuse large cell lymphoma.…”

CCND2 rearrangements are the most frequent genetic events in cyclin D1− mantle cell lymphoma

“…12,13 The SOX11 transcription factor has been found to be a reliable and highly specific biomarker for conventional cyclin D1 ϩ MCL. In addition, it is not expressed in other low-grade B-cell lymphomas, offering a valuable practical tool to properly recognize cases of cyclin D1 Ϫ MCL 12,[14][15][16][17][18][19] that were previously only identified by GEP.…”

New developments in the pathology of malignant lymphoma: a review of the literature published from October 2009 to January 2010

“…Metcalf et al [41] looked for the specificity of cycln D1, D2, and D3 in over 700 lymphoma samples. In their series, all MCL were cyclin D1-positive and few DLBL as well.…”