Abstract
Lack of apoptosis has been linked to prolonged survival of malignant B cells expressing bcl-2. The aim of the present study was to analyze the amount of bcl-2 protein expressed along normal human B-cell maturation and to establish the frequency of aberrant bcl-2 expression in B-cell malignancies. In normal bone marrow (n=11), bcl-2 expression obtained by quantitative multiparametric flow cytometry was highly variable: very low in both CD34+ and CD34− B-cell precursors, high in mature B-lymphocytes and very high in plasma cells. Bcl-2 expression of mature B-lymphocytes from peripheral blood (n=10), spleen (n=8) and lymph node (n=5) was significantly higher (P<0.02) in CD23− as compared to CD23+ B cells, independent of the type of tissue analyzed. Upon comparison with normal human B-cell maturation, bcl-2 expression in neoplastic B cells from 144 patients was found to be aberrant in 66% of the cases, usually corresponding to bcl-2 overexpression (63%). Follicular lymphoma (FL) carrying t(14;18) and MALT lymphoma were the only diagnostic groups constantly showing overexpression of bcl-2. Bcl-2 overexpression was also frequently found in precursor B-acute lymphoblastic leukemia (84%), typical (77%) and atypical (75%) B-cell chronic lymphocytic leukemia, prolymphocytic leukemia (two of three cases), mantle cell lymphoma (55%), but not in t(14;18)− FL, splenic marginal zone lymphoma, Burkitt lymphoma and multiple myeloma.
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References
Cory S . Regulation of lymphocyte survival by the bcl-2 gene family. Annu Rev Immunol 1995; 13: 513–543.
Williams GT . Programmed cell death: apoptosis and oncogenesis. Cell 1991; 65: 1097–1098.
Vaux DL, Cory S, Adams JM . Bcl-2 gene promotes hematopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988; 335: 440–442.
Hockenbery D, Nuñez G, Milliman C, Schreiber RD, Korsmeyer SJ . Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990; 348: 334–346.
Nuñez G, London L, Hockenbery D, Alexander M, Mckean JP, Korsmeyer SJ . Deregulated bcl-2 gene expression selectively prolongs survival of growth factor-deprived hematopoietic cell lines. J Immunol 1990; 144: 3602–3610.
Oltvai ZN, Milliman CL, Korsmeyer SJ . Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74: 609–619.
Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM . Cloning of the chromosome breakpoint of neoplastic B-cells with the t(14;18) chromosomal translocation. Science 1984; 226: 1097–1099.
Ngan BY, Chen-Levy Z, Weiss LM, Warke RA, Cleary ML . Expression in non-Hodgkin's lymphoma of the bcl-2 protein associated with the t(14;18). N Engl J Med 1988; 318: 1638–1644.
McDonnell TJ, Deane N, Platt FM . Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 1989; 57: 79–88.
McDonnell TJ, Korsmeyer SJ . Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 1991; 349: 254–256.
Adams JM, Cory S . The bcl-2 protein family: arbiters of cell survival. Science 1998; 281: 1322–1326.
Pezzella F, Tse AGD, Cordell JL, Pulford KAF, Gatter KC, Masson KY . Expression of the bcl-2 protein is not specific for the 14;18 chromosomal translocation. Am J Pathol 1990; 137: 225–232.
Schena M, Larsson LG, Gottardi, Gaidano G, Carlsson M, Nilsson K et al. Growth and differentiated associated expression of bcl-2 in B chronic lymphocytic leukemia cells. Blood 1992; 79: 2981–2989.
Adachi M, Tefferi A, Greipp PR, Kipps TJ, Tsujimoto Y . Preferential linkage of bcl-2 to immunoglobulin light chain gene in chronic lymphocytic leukemia. J Exp Med 1990; 171: 559–564.
Piris MA, Pezzella F, Garcia-Montero JC, Orradre JL, Villuendas R, Sanchez-Beato M et al. p53 and bcl-2 expression in high grade B lymphomas: correlation with survival time. Br J Cancer 1994; 69: 337–341.
Hill M, MacLenan A, Cunningham DC, Vaudhan D, Burke M, Clarke P et al. Prognostic significant of bcl-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin lymphoma: A British National Lymphoma Investigation Study. Blood 1996; 88: 1046–1051.
Hamilton MS, Barker HF, Ball J, Drew M, Abbot SD, Franklin IM . Normal and neoplastic plasma cells express the bcl-2 antigen. Leukemia 1991; 5: 568–571.
Ladanyi M, Wang S, Niesvizky R, Feiner H, Michaeli J . Proto-oncogene analysis in multiple myeloma. Am J Pathol 1992; 141: 949–953.
Miguel-García A, Orero T, Matutes E, Carbonell F, Miguel-Sosa A, Linares M et al. Bcl-2 expression in plasma cells from neoplastic gammopathies and reactive plasmacytosis: a comparative study. Haematologica 1998; 83: 298–304.
Campana D, Coustan Smith E, Manabe A, Buschle M, Raimondi SC, Behm FG et al. Prolonged survival of B-lineage lymphoblastic leukemia cells is accompanied by overexpression of bcl-2 protein. Blood 1993; 81: 1025–1031.
Harris N, Jaffe E, Diebold J, Flandrin G, Muller-Hermelink H, Vardiman I et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting-Airline House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835–3849.
Harris N, Jaffe E, Stein H, Banks PM, Chan JKC, Clearly ML et al. A revised European–American classification of lymphoid neoplasms: a proposal from the International Lymphoma study Group. Blood 1994; 84: 1361–1392.
Benito GE, Sanchez ML, Del Pino-Montes J, Calvo JJ, Menendez P, Garcia-Marcos MA et al. A new cytometric method for the immunophenotypic characterization of bone-derived human osteoclasts. Cytometry 2002; 49: 261–266.
Menéndez P, Caballero MD, Prosper F, Cañizo MC, Pérez-Simón JA, Mateos MV et al. The composition of the leukapheresis products impacts on the hematopoietic recovery after autologous transplantation independently of the mobilization regimen. Transfusion 2002; 42: 1159–1172.
Kappelmayer J, Gratama JW, Karaszi E, Menéndez P, Ciudad J, Rivas R et al. Flow cytometry detection of intracellular myeloperoxidase, CD3 and CD79a: interaction between monoclonal antibody clones, fluorochromes and sample preparation protocols. J Immunol Methods 2000; 242: 53–65.
Lima M, Teixeira Mdos A, Dos Santos AH, Queirós ML, Justiça B . Decreased expression of bcl-2 (p26) in CD8(+) lymphocytes of patients with T-cell lymphoproliferative disorders of large gran lymphocytes. Hematol Oncol 1997; 15: 81–91.
Hockenbery DM, Zutter M, Hickey W, Nahm M, Korsmeyer S . Bcl-2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci USA 1991; 88: 6961–6965.
DiGiuseppe JA, Lebeau P, Augenbraun J, Borowitz MJ . Multiparameter flow cytometric analysis of bcl-2 and Fas expression in normal and neoplastic hematopoiesis. Am J Clin Pathol 1996; 106: 345–351.
Cerveró C, Escribano L, San Miguel JF, Diaz-Agustin B, Bravo P, Villarrubia J et al. Expression of bcl-2 by human bone marrow mast cells and its over expression in mast cell leukemia. Am J Hematol 1999; 60: 191–195.
MacLennan IC . Germinal centers. Annu Rev Immunol 1994; 12: 117–139.
Bonnefoy JY, Lecoanet-Henchoz S, Aubry JP, Gauchat JF, Graber P . CD23 and B-cell activation. Curr Opin Immunol 1995; 3: 355–359.
Nuñez G, Hockenbery D, McDonnell TJ, Sorensen CM, Korsmeyer SJ . Bcl-2 maintains B cell memory. Nature 1991; 353: 71–73.
Rolink A, Melchers F . Molecular and cellular origins of B lymphocyte diversity. Cell 1991; 66: 1081–1094.
Falini B, Mason DY . Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. Blood 2002; 99: 409–426.
Pezzella F, Gatter KC, Mason DY, Bastard C, Duval C, Krajewski A et al. Bcl-2 protein expression in follicular lymphomas in absence of 14;18 translocation. Lancet 1990; 336: 1510–1511.
Seite P, Hillion J, d'Agay MF, Gaulard P, Cazals D, Badoux F et al. Bcl- gene activation and protein expression in a follicular lymphoma: a report of 64 cases. Leukemia 1993; 3: 410–417.
Sanchez-Beato M, Sanchez-Aguilera A, Piris MA . Cell cycle deregulation in B-cell lymphomas. Blood 2003; 101: 1220–1235.
Hofmann WK, de Vos SK, Wachsman W, Pinkus GS, Said JW, Koeffler HP . Altered apoptosis pathways in mantle cell lymphoma detected by oligonucleotide microarray. Blood 2001; 98: 787–794.
Ong F, Nieuwkoop JA, Groot-Sswings GMJS, Hermans J, Harvey MS, Kluin PM et al. Bcl-2 protein expression is not related to short survival in multiple myeloma. Leukemia 1995; 9: 1282–1284.
Peréz-Simón JA, García-Sanz R, Tabernero MD, Almeida J, Gonzalez M, Fernandez-Calvo J et al. Prognostic value of numerical chromosome aberrations in multiple myeloma: a FISH analysis of 15 different chromosomes. Blood 1998; 91: 3366–3371.
Tricot G, Barlogie B, Jagannath S, Bracy D, Mattox S, Vesole DH et al. Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood 1995; 86: 4250–4256.
Acknowledgements
P Menéndez was supported by a grant from Fondo de Investigaciones Sanitarias, Madrid, Spain (FIS, BEFI 98/9669). This work was supported in part by a grant from the Red Temática “Mieloma mùltiple y otras gammapatias monoclonales”. Fondo de Investigación Sanitaria, Ministerio de Sanidad y Consumo, Madrid, Spain.
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Menendez, P., Vargas, A., Bueno, C. et al. Quantitative analysis of bcl-2 expression in normal and leukemic human B-cell differentiation. Leukemia 18, 491–498 (2004). https://doi.org/10.1038/sj.leu.2403231
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DOI: https://doi.org/10.1038/sj.leu.2403231
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