D cyclins in CD5+ B-cell lymphoproliferative disorders: cyclin D1 and cyclin D2 identify diagnostic groups and cyclin D1 correlates with ZAP-70 expression in chronic lymphocytic leukemia.

We analyzed protein expression of cyclin D1, cyclin D2, and cyclin D3 using high-resolution enzymatic amplification staining and flow cytometry in the neoplastic cells from 80 patients with CD5+ B-cell lymphoproliferative disorders. The D cyclins were expressed differentially in chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), and mantle cell lymphoma (MCL) with strong staining of cyclin D1 and D2 in MCL, strong staining of cyclin D1 but weak staining of cyclin D2 in 4 of 5 PLLs, and low-level staining for both cyclins in most CLLs. No correlation between cyclin D1 and D2 and growth rates or CD38 expression was observed. However, cyclin D1 levels were significantly higher in ZAP-70+ CLL cases, although no association between ZAP-70 and cyclin D2 was detected. The results indicate that flow cytometric analysis of D cyclins may help in classification of CD5+ B-cell lymphoproliferative disorders.

[1]  S. Sharma,et al.  Latent membrane protein-1 induces cyclin D2 expression, pRb hyperphosphorylation, and loss of TGF-beta 1-mediated growth inhibition in EBV-positive B cells. , 1995, Journal of immunology.

[2]  J. LaBaer,et al.  New functional activities for the p21 family of CDK inhibitors. , 1997, Genes & development.

[3]  Steven L. Allen,et al.  Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. , 1999, Blood.

[4]  E. Jaffe,et al.  Use of CD23 (BU38) on paraffin sections in the diagnosis of small lymphocytic lymphoma and mantle cell lymphoma. , 1996, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[5]  J. Diehl,et al.  p21Cip1 Promotes Cyclin D1 Nuclear Accumulation via Direct Inhibition of Nuclear Export* , 2002, The Journal of Biological Chemistry.

[6]  M. Seto,et al.  The Positive Nuclear Staining Observed with Monoclonal Antibody against PRAD1/Cyclin D1 Correlates with mRNA Expression in Mantle Cell Lymphoma , 1995, Japanese journal of cancer research : Gann.

[7]  T. Tsubata,et al.  B cell signaling. Introduction. , 2001, International reviews of immunology.

[8]  L. Staudt,et al.  Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. , 2004, Blood.

[9]  Adrian Wiestner,et al.  ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. , 2003, Blood.

[10]  C. Stewart,et al.  Phenotypic heterogeneity of B cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. , 2003, American journal of clinical pathology.

[11]  D. Catovsky,et al.  The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. , 1994, Leukemia.

[12]  L. Klein-Hitpass,et al.  Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia , 2005, Leukemia.

[13]  K. Lee,et al.  Differential expression of p16/p21/p27 and cyclin D1/D3, and their relationships to cell proliferation, apoptosis, and tumour progression in invasive ductal carcinoma of the breast , 2001, The Journal of pathology.

[14]  J. Slingerland,et al.  Multiple Roles of the PI3K/PKB (Akt) Pathway in Cell Cycle Progression , 2003, Cell cycle.

[15]  S. Proctor,et al.  The Prognostic Value of CD38 Expression and its Quantification in B Cell Chronic Lymphocytic Leukemia (B-CLL) , 2004, Leukemia & lymphoma.

[16]  M. N. Kilo,et al.  The utility of flow cytometric immunophenotypic analysis in the distinction of small lymphocytic lymphoma/chronic lymphocytic leukemia from mantle cell lymphoma. , 1996, American journal of clinical pathology.

[17]  Emili Montserrat,et al.  ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. , 2003, The New England journal of medicine.

[18]  E. Schuuring,et al.  Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma. , 1995, Blood.

[19]  M. Roussel,et al.  Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. , 1998, Genes & development.

[20]  P. Marynen,et al.  Molecular characterization of 12p abnormalities in hematologic malignancies: deletion of KIP1, rearrangement of TEL, and amplification of CCND2. , 1996, Blood.

[21]  H. Kantarjian,et al.  Detection of subgroups of chronic B-cell leukemias by FMC7 monoclonal antibody. , 1994, American journal of clinical pathology.

[22]  D. Catovsky,et al.  Detection of cyclin D1 in B cell lymphoproliferative disorders by flow cytometry , 2002, Journal of clinical pathology.

[23]  D. Catovsky,et al.  Heterogeneity of B-cell leukemias demonstrated by the monoclonal antibody FMC7 , 1981 .

[24]  H. Merz,et al.  Aberrant Immunophenotypes of Mantle Cell Lymphomas , 2003, Leukemia & lymphoma.

[25]  N. Harris,et al.  Cyclin D1 (Bcl-1, PRAD1) protein expression in low-grade B-cell lymphomas and reactive hyperplasia. , 1994, The American journal of pathology.

[26]  J. Chan,et al.  Consistent Immunostaining for Cyclin D1 Can Be Achieved on a Routine Basis Using a Newly Available Rabbit Monoclonal Antibody , 2004, The American journal of surgical pathology.

[27]  M. Hurme,et al.  Surface antigen expression in chronic lymphocytic leukemia: clustering analysis, interrelationships and effects of chromosomal abnormalities , 2002, Leukemia.

[28]  N. Harris,et al.  Expression of cyclin D1 protein in centrocytic/mantle cell lymphomas with and without rearrangement of the BCL1/cyclin D1 gene. , 1995, Human pathology.

[29]  G. Pinkus,et al.  Distinction between small lymphocytic and mantle cell lymphoma by immunoreactivity for CD23. , 1994, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[30]  L. Ginaldi,et al.  Levels of expression of CD19 and CD20 in chronic B cell leukaemias. , 1998, Journal of clinical pathology.

[31]  H. Kantarjian,et al.  Variations in the low levels of cyclin D1/BCL1 have prognostic value in chronic lymphocytic leukemia. , 2000, Leukemia research.

[32]  M. Younes,et al.  Optimized cyclin D1 immunoperoxidase staining in mantle cell lymphoma. , 2000, Applied immunohistochemistry & molecular morphology : AIMM.

[33]  L. Rassenti,et al.  ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. , 2005, Blood.

[34]  N. Harris,et al.  Cyclin D1 expression in non-Hodgkin's lymphomas. Detection by immunohistochemistry. , 1995, American journal of clinical pathology.

[35]  F. Zindy,et al.  Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. , 1997, Genes & development.

[36]  D. Kaplan.  Enzymatic Amplification Staining for Cell Surface Antigens , 2003, Current protocols in cytometry.

[37]  H. Meyerson,et al.  D cyclins in lymphocytes , 2005, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[38]  Simon C Watkins,et al.  Current Protocols In Cytometry , 1997 .

[39]  T. Kipps,et al.  Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Arthur Weiss,et al.  Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. , 2002, Blood.

[41]  D. Neal,et al.  Cyclin D1 expression in transitional cell carcinoma of the bladder: correlation with p53, waf1, pRb and Ki67 , 2001, British Journal of Cancer.

[42]  D. Catovsky,et al.  Improvement of the chronic lymphocytic leukemia scoring system with the monoclonal antibody SN8 (CD79b). , 1997, American journal of clinical pathology.

[43]  B. Sola,et al.  Transcriptional and post‐transcriptional mechanisms induce cyclin‐D1 over‐expression in B‐chronic lymphoproliferative disorders , 1999, International journal of cancer.

[44]  L. Medeiros,et al.  Mature B-cell leukemias with more than 55% prolymphocytes. A heterogeneous group that includes an unusual variant of mantle cell lymphoma. , 2001, American journal of clinical pathology.

[45]  R. Scolyer,et al.  The significance of the Wnt pathway in the pathology of human cancers. , 2004, Pathology.

[46]  F Solé,et al.  Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies. , 2001, Blood.

[47]  E. Berg,et al.  World Health Organization Classification of Tumours , 2002 .

[48]  M. Raffeld,et al.  bcl-1, t(11;14), and mantle cell-derived lymphomas. , 1991, Blood.

[49]  Shigeo Nakamura,et al.  Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma , 2000 .

[50]  L. Staudt,et al.  The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. , 2003, Cancer cell.

[51]  A. Tefferi,et al.  Heterogeneity and clinical relevance of the intensity of CD20 and immunoglobulin light-chain expression in B-cell chronic lymphocytic leukemia. , 1996, American journal of clinical pathology.

[52]  D. Catovsky,et al.  Cyclin D1 by flow cytometry as a useful tool in the diagnosis of B-cell malignancies. , 2001, Leukemia research.

[53]  Laird Ak.  DYNAMICS OF TUMOR GROWTH. , 1964 .

[54]  C. Ross,et al.  Cyclin D1 protein expression in mantle cell lymphoma. , 1995, Annals of oncology : official journal of the European Society for Medical Oncology.

[55]  J. Plate.  PI3-Kinase Regulates Survival of Chronic Lymphocytic Leukemia B-Cells by Preventing Caspase 8 Activation , 2004, Leukemia & lymphoma.

[56]  E. Lam,et al.  BCR targets cyclin D2 via Btk and the p85α subunit of PI3-K to induce cell cycle progression in primary mouse B cells , 2003, Oncogene.

[57]  Rosario Giustolisi,et al.  The clinical and diagnostic relevance of CD23 expression in the chronic lymphoproliferative disease , 2002, Cancer.

[58]  E. Jaffe.  Pathology and Genetics: Tumours of Haematopoietic and Lymphoid Tissues , 2003 .

[59]  J. Chan,et al.  Nucleolated variant of mantle cell lymphoma with leukemic manifestations mimicking prolymphocytic leukemia. , 2002, American journal of clinical pathology.

[60]  G. Vance,et al.  Chronic lymphocytic leukemia/small lymphocytic lymphoma with trisomy 12 and focal cyclin d1 expression: a potential diagnostic pitfall. , 2009, Archives of pathology & laboratory medicine.

[61]  F. Ajchenbaum‐Cymbalista,et al.  Overexpression of cyclin D2 in chronic B-cell malignancies. , 1995, Blood.