BCL-2 in B-Chronic Lymphocytic Leukemia

  • F. Caligaris-Cappio
  • P. Ghia
  • D. Gottardi
  • G. Parvis
  • M. G. Gregoretti
  • K. Nilsson
  • M. Schena
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 182)


B-chronic lymphocytic leukemia (B-CLL) is a human B-cell malignancy characterized by the relentless accumulation of long-lived mature B cells that have two distinctive features. First, more than 99% of the circulating malignant lymphocytes are in the Go phase of the cell cycle (Andreeff et al. 1980; Carlsson et al. 1988). Second, B-CLL cells express the CDS surface molecule (Caligaris-Cappio and Janossy 1985). Crucial to our understanding of the development and natural history of the disease is to define which is the cellular origin of B-CLL and which mechanisms favour the progressive accumulation of malignant resting CD5+ B cells. The phenotype of B-CLL cells (Caligaris-Cappio and Janossy 1985, Freedman and Nadler 1990; Schena et al. 1992) suggests a similarity with mature B lymphocytes that are found in the mantle zone of secondary follicles and lends credit to the hypothesis that the normal counterpart of B-CLL may be a long-lived, recirculating subpopulation of mantle zone B cells (Galton and MacLennan 1982). As, in adult lymphoid tissues, CD5+ B lymphocytes are located within the mantle zone of secondary follicles (Kipps et al. 1991) it is not unreasonable, though still unproven, to suggest that the CD5+ B cell population might be the actual normal counterpart of B-CLL.


Chronic Lymphocytic Leukemia Secondary Follicle Mantle Zone Major Breakpoint Region Human Follicular Lymphoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adachi M, Tefferi A, Greipp PR, Kipps J, Tsujimoto Y (1990) Preferential linkage of BCL-2 to Immunoglobulin light chain gene in chronic lymphocytic leukemia. J Exp Med 171:559–564.PubMedCrossRefGoogle Scholar
  2. Andreeff M, Darzynkiewicz Z, Sharpless TK. Clarkson BD, Melamed MR (1980) Discrimination of human leukemia subtypes by flow cytometric analysis of cellular DNA and RNA. Blood 55:282–289.PubMedGoogle Scholar
  3. Antin JH, Emerson SG, Martin P, Gadol N. Ault K (1986) Leu-1+ (CD5+) B cells. A major lymphoid subpopulation in human fetal spleen: phenotypic and functional studies. J Immunol 136:505–510.PubMedGoogle Scholar
  4. Bakhshi A A, Jensen JP. Goldman P, Wright JJ, McBride W, Epstein AL, Korsmeyer SJ (1985) Cloning the chromosomal breakpoint of t(14;18) human lymphomas: Clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41:899–906..PubMedCrossRefGoogle Scholar
  5. Bergui L, Tesio L. Schena M, Riva M, Malavasi F, Schulz T, Marchisio PC, Caligaris-Cappio F (1988) CD5 and CD21 molecules are a functional unit in the cell/substrate adhesion of B-CLL. Eur J Immunol 18: 89–96.PubMedCrossRefGoogle Scholar
  6. Caligaris-Cappio F, Janossy G (1985) Surface markers in chronic lymphoid leukemias of B cell type. Seminars in Hematol 22:1–12.Google Scholar
  7. Carlsson M, Totterman TH, Matsson P, Nilsson K (1988) Cell cycle progression of B-chronic lymphocytic leukemia cells induced to differentiate by TPA. Blood 71:415–421.PubMedGoogle Scholar
  8. Chen-Lew Z, Nourse J. Cleary ML (1989) The bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14; 18) translocation. Mol Cell Biol 9:701–710..Google Scholar
  9. Cleary ML, Sklar J (1985) Nucleotide sequence of a t(14:18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionaily active locus on chromosome 18. Proc Natl Acad Sci. USA 82:7439–7443.PubMedCrossRefGoogle Scholar
  10. Cleary ML, Smith SD, Sklar J (1986) Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/Immunoglobulin transcript resulting from the t(14; 18) translocation. Cell 47:19–28.PubMedCrossRefGoogle Scholar
  11. Dyer MJS. Fischer P, Nacheva E. Labastide W, Karpas A (1990) A new human B-cell non-Hodgkin’s lymphoma cell line (Karpas 422) exhibiting both t(14;18) and t(4;11) chromosomal translocations. Blood 75:709–714.PubMedGoogle Scholar
  12. Freedman AS, Nadler LM (1990) The relationship of chronic lymphocytic leukemia to normal activated B cells. Leuk Lymph 1:293–298.CrossRefGoogle Scholar
  13. Galton DAG. MacLennan ICM (1982) Clinical patterns of B cell malignancy. Clin Hematol 11:561–587.Google Scholar
  14. Ghigo D. Gaidano GL. Treves S. Bussolino F, Pescarmona G, Caligaris-Cappio F, Bosia A (1991) Na+/H+ antiporter has different properties in human B lymphocytes according to CD5 expression and malignant phenotype. Eur J Immunol 21:583–588.PubMedCrossRefGoogle Scholar
  15. Graninger WB. Seto M, Boutain B, Goldman P, Korsmeyer SJ (1987) Expression of bcl-2 and bcl-2-Ig fusion transcripts in normal and neoplastic cells. J Clin Invest 80:1512–1515.PubMedCrossRefGoogle Scholar
  16. Hockenbery D, Nunez G, Milliman C, Schreiber D, Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336.PubMedCrossRefGoogle Scholar
  17. Kipps TJ, Duffy SF (1991) Relationship of the CD5 B cell to human tonsillar B lymphocytes that express autoantibody-associated cross-reactive idiotypes. J Clin Invest 87:2087–2095.PubMedCrossRefGoogle Scholar
  18. Korsmeyer SJ. McDonnell TJ, Nunez G, Hockenbery D, Young R (1990) Bcl-2: B cell life, death and neoplasia. Current Topics in Microbiol Immunol 166:203–211.CrossRefGoogle Scholar
  19. Liu YJ, Mason DY, Johnson GD, Abbot S, Gregory CD, Hardie DL, Gordon J. MacLennan ICM (1991) Germinal center cells express bcl-2-protein after activation by signals which prevent their entry to apoptosis. Eur J Immunol 21:1905–1910.PubMedCrossRefGoogle Scholar
  20. Marchisio PC, Bergui L, Corbascio G, D’Urso N, Tesio L, Schena M, Caligaris-Cappio F (1988) LFA1, vinculin and talin co-localization at specific adhesion sites in the malignant B lymphocytes of B-CLL. Blood 72:830–833.PubMedGoogle Scholar
  21. McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U. McKearn JP, Korsmeyer SJ (1989) bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57:79–88.PubMedCrossRefGoogle Scholar
  22. Nunez G, London L, Hockenbery D, Alexander M, McKearn JP, Korsmeyer SJ (1990) Deregulated bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol 144:3602–3610.PubMedGoogle Scholar
  23. Nunez G, Hockenberry D, McDonnell TJ. Sorensen CM, Korsmeyer SJ (1991) Bcl-2 maintains B cell memory. Nature 353: 71–73.PubMedCrossRefGoogle Scholar
  24. Pezzella F, Tse AGD, Cordell JL. Pulford KAF, Gatter C, Mason DY (1990) Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol 137:225–232.PubMedGoogle Scholar
  25. Raghobier S, van Krieken JHJM, Kluin-Nelemans JC, Gillis A, van Ommen GJB. Ginsberg AM, Raffeld M, Kluin PM (1991) Oncogene rearrangements in chronic B-cell leukemia. Blood 77:1560–1564.Google Scholar
  26. Rai KR, Sawitsky A, Cronkite EP, Chanana D, Levy RN, Pasternack BS (1975) Clinical staging of chronic lymphocytic leukemia. Blood 46:219–234.PubMedGoogle Scholar
  27. Reed JC, Tsujimoto Y, Alpers JD, Croce M, Nowell PC (1987) Regulation of bcl-2 protooncogene expression during normal human lymphocyte proliferation. Science 236:1295–1299.PubMedCrossRefGoogle Scholar
  28. Schena M, Gaidano G, Gottardi D, Malavasi F, Larsson LG, Nilsson K, Caligaris-Cappio F (1992) Molecular investigation of the cytokines produced by normal and malignant B lymphocytes. Leukemia 2:120–125.Google Scholar
  29. Schena M, Larsson LG, Gottardi G, Gaidano G, Carlsson M, Nilsson K. Caligaris-Cappio F (1992) Growth and differentiation-associated expression of BCL-2 in B-chronic lymphocytic leukemia cells. Blood, in press.Google Scholar
  30. Seto M, Jaeger U. Hocket RD, Graninger W, Bennett S, Goldman P, Korsmeyer SJ (1988) Alternative promoters and exons, somatic mutation and deregulation of the bcl-2-Ig fusion gene in lymphoma. EMBO J 7:123–131.PubMedGoogle Scholar
  31. Tsujimoto Y, Finger LR, Yunis J, Nowell C, Croce CM (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226: 1097–1099.PubMedCrossRefGoogle Scholar
  32. Tsujimoto Y. Croce CM (1986) Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc Natl Acad Sci. USA 83: 5214–5418.PubMedCrossRefGoogle Scholar
  33. Tsujimoto Y, Bashir MM, Givol I, Cossman J, Jaffe E, Croce CM (1987) DNA rearrangements in human follicular lymphoma can involve the 5′ or the 3′ region of the bcl-2 gene. Proc Natl Acad Sci. USA 84:1329–1331.PubMedCrossRefGoogle Scholar
  34. Tanaka S., Louie D.C., Kant J.A. and Reed J.C. (1992) Frequent incidence of somatic mutations in the translocated BCL2 oncogenes of non-Hodgkin’s lymhomas. Bllod 79:229–237.Google Scholar
  35. Vaux DL, Cory S, Adams JM (1988) bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335:440–442.PubMedCrossRefGoogle Scholar
  36. Zutter M, Hockenberry D. Silverman GA, Korsmeyer SA (1991) Immunolocalization of the Bcl-2 protein within hematopoietic neoplasms. Blood 78:1062–1068.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • F. Caligaris-Cappio
    • 1
  • P. Ghia
    • 1
  • D. Gottardi
    • 1
  • G. Parvis
    • 1
  • M. G. Gregoretti
    • 1
  • K. Nilsson
    • 2
  • M. Schena
    • 1
  1. 1.Dipartimento di Scienze Biomediche e Oncologia UmanaUniversità di TorinoTorinoItaly
  2. 2.Department of PathologyUniversity of UppsalaUppsalaSweden

Personalised recommendations