title: 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 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 cyclin-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 the 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. Cyclin-D1, D2 and D3 were expressed in 100, 22 and 6% of mantle-cell lymphomas and 2, 49 and 20% of diffuse large B-cell lymphomas. 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-cell and natural killer cell lymphomas and acute myeloid leukemias also expressed cyclin-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.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Metcalf
authors.forename: Shuchun
authors.initials: S
authors.lastname: Zhao
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Anderson
authors.forename: Zhi Shun
authors.initials: ZS
authors.lastname: Lu
authors.forename: Ilana
authors.initials: I
authors.lastname: Galperin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Marinelli
authors.forename: Athena M
authors.initials: AM
authors.lastname: Cherry
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Natkunam
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism*; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism* / Q000473:pathology; D008297:Male; D046888:Tissue Array Analysis; D014178:Translocation, Genetic
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; C080336:CCND2 protein, human; C534696:CCND3 protein, human; D056742:Cyclin D2; D056743:Cyclin D3; D007143:Immunoglobulin Heavy Chains; D019938:Cyclin D1