Medical Oncology

, Volume 15, Issue 4, pp 234–240 | Cite as

Apoptosis in B-chronic lymphocytic leukaemia

  • Lyda M OsorioEmail author
  • Miguel Aguilar-Santelises


B-chronic lymphocytic leukaemia (B-CLL) is characterised by the progressive accumulation of monoclonal B cells, which may be the result of several factors leading to extended B-CLL cell lifespan, increased proliferative capacity and diminished cell death. Here we review the implications of several signals mediated by receptors, such as surface IgM, CD6 and CD40, for the B-CLL cell survival, together with data on gene modulation in relation to the apoptosis process in B-CLL cells. We also describe some features of the Fas/FasL system in B-CLL that hypothetically might contribute to the accumulation of leukaemic cells and the progressions of the disease, by downregulating the apoptotic response or avoiding the autologous immune response.


B-CLL apoptosis Fas/FasL Bcl-2 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development.Cell 1997;88: 347–354.PubMedCrossRefGoogle Scholar
  2. 2.
    Green DR, Scott DW. Activation-induced apoptosis in lymphocytes.Curr Opin Immunol 1994;6: 476–487.PubMedCrossRefGoogle Scholar
  3. 3.
    Strasser A. Life and death during lymphocyte development and function: evidence for two distinct killing mechanisms.Curr Opin Immunol 1995;7: 228–234.PubMedCrossRefGoogle Scholar
  4. 4.
    van Parijs L, Abbas AK. Homeostasis and self-tolerance in the immune system: turning lymphocytes off.Science 1998;280: 243–248.PubMedCrossRefGoogle Scholar
  5. 5.
    Cohen JJ, Duke RC. Apoptosis and programmed cell death in immunity.Ann Rev Immunol 1992;10; 2676–2693.CrossRefGoogle Scholar
  6. 6.
    Kroemer G, Zamzami N, Susin SA. Mitochondrial control of apoptosis.Immunol Today 1997;18: 44–51.PubMedCrossRefGoogle Scholar
  7. 7.
    Golstein P. Controlling cell death.Science 1997;275: 1081–1082.PubMedCrossRefGoogle Scholar
  8. 8.
    Nicholson DW, Thornberry NA. Caspases: killer proteases.TIBS 1997;22: 299–306.PubMedGoogle Scholar
  9. 9.
    Cory S. Regulation of lymphocyte survival by the Bcl-2 gene family.Annu Rev Immunol 1995;13: 513–543.PubMedCrossRefGoogle Scholar
  10. 10.
    Nagata S. Apoptosis by death factor.Cell 1997;88: 355–365.PubMedCrossRefGoogle Scholar
  11. 11.
    Collins RJet al. Spontaneous programmed death (apoptosis) of B-chronic lymphocytic leukaemia cells following their culturein vitro.Br J Haematol 1989;71: 343–350.PubMedCrossRefGoogle Scholar
  12. 12.
    Corcione Aet al. Expression of granulocyte colony-stimulating factor and granulocyte colony-stimulating factor receptor genes in partially overlapping monoclonal B-cell populations from chronic lymphocytic leukemia patients.Blood 1996;87: 2861–2869.PubMedGoogle Scholar
  13. 13.
    Francia di Celle Pet al. Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion.Blood 1996;87: 4382–4389.PubMedGoogle Scholar
  14. 14.
    Tangye SG, Raison RL. Human cytokines suppress apopotosis of leukaemic CD5+ B cells and preserve expression of bcl-2.Immunol Cell Biol 1997;75: 127–135.PubMedCrossRefGoogle Scholar
  15. 15.
    König Aet al. Basic fibroblast growth factor (bFGF) upregulates the expression of bcl-2 in B cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis.Leukemia 1997;11: 258–265.PubMedCrossRefGoogle Scholar
  16. 16.
    Osorio LM, Jondal M, Aguilar-Santelises M. Regulation of B-CLL apoptosis through membrane receptors and Bcl-2 family proteins.Leuk Lymphom 1998;30: 247–256.Google Scholar
  17. 17.
    Panayiotidis P, Jones D, Ganeshaguru K, Foroni L, Hoffbrand AV. Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cellsin vitro.Br J Haematol 1996;92: 97–103.PubMedCrossRefGoogle Scholar
  18. 18.
    Langneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P. Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells.Blood 1998;91: 2387–2396.Google Scholar
  19. 19.
    McConkey DJet al. Induction of DNA fragmentation in chronic B-lymphocytic leukemia cells.J Immunol 1991;146: 1072–1076.PubMedGoogle Scholar
  20. 20.
    Igarashi Het al. B cell Ag receptor mediates different types of signals in the protein kinase activity between immature B cell and mature B cell.J Immunol 1994;153: 2381–2393.PubMedGoogle Scholar
  21. 21.
    Robertson LEet al. Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-beta-D-arabinosyl-2-fluoroadenine.Blood 1993;81: 143–150.PubMedGoogle Scholar
  22. 22.
    Begleiter A, Lee K, Israels LG, Mowat MR, Johnston JB. Chlorambucil induced apoptosis in chronic lymphocytic leukemia (CLL) and its relationship to clinical efficacy.Leukemia 1994;8: S103–106.PubMedGoogle Scholar
  23. 23.
    Mainou-Fowler T, Craig VA, Copplestone JA, Hamon MD, Prentice AG. Interleukin-5 (IL-5) increases spontaneous apoptosis of B-cell chronic lymphocytic leukemia cellsin vitro independently of bcl-2 expression and is inhibited by IL-4.Blood 1994;84: 2297–2304.PubMedGoogle Scholar
  24. 24.
    Fluckiger AC, Durand I, Banchereau J. Interleukin 10 induces apoptotic cell death of B-chronic lymphocytic leukemia cells.J Exp Med 1994;179: 91–99.PubMedCrossRefGoogle Scholar
  25. 25.
    Mentz Fet al. Theophylline synergizes with chlorambucil in inducing apoptosis of B-chronic lymphocytic leukemia cells.Blood 1996;88: 2172–2182.PubMedGoogle Scholar
  26. 26.
    Binet JLet al. What does apoptosis mean in CLL?Leuk Lymphoma 1996;22: 47–52.PubMedCrossRefGoogle Scholar
  27. 27.
    Aguilar-Santelises M, Rottenberg ME, Lewin N, Mellstedt H, Jondal M. Bcl-2, Bax and p53 expression in B-CLL in relation toin vitro survival and clinical progression.Int J Cancer 1996;69: 114–119.PubMedCrossRefGoogle Scholar
  28. 28.
    Consoli Uet al. Differential induction of apoptosis by fludarabine monophosphate in leukemic B and normal T cells in chronic lymphocytic leukemia.Blood 1998;95: 1742–1748.Google Scholar
  29. 29.
    Bellosillo B, Dalmau M, Colomer D, Gil J. Involvement of CED-3/ICE proteases in the apoptosis of B-chronic lymphocytic leukemia cells.Blood 1997;89: 3378–3384.PubMedGoogle Scholar
  30. 30.
    Chandra Jet al. Protease activation is required for glucocorticoid-induced apoptosis in chronic lymphocytic leukemic lymphocytes.Blood 1997;90: 3673–3681.PubMedGoogle Scholar
  31. 31.
    Krajewski Set al. Immunolocalization of the ICE/Ced-3-family protease, CPP32 (Caspase-3), in non-Hodgkin's lymphomas, chronic lymphocytic leukemias, and reactive lymph nodes.Blood 1997;89: 3817–3825.PubMedGoogle Scholar
  32. 32.
    Beg AA, Baltimore D. An essential role for NFkB in preventing TNFα-induced cell death.Science 1996;274: 782–784.PubMedCrossRefGoogle Scholar
  33. 33.
    Wu Met al. Inhibition of NFkB/Rel induces apoptosis of murine B cells.EMBO J 1996;15: 4682–4690.PubMedGoogle Scholar
  34. 34.
    Delic Jet al. The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-α-initiated apoptosis.Br J Cancer 1998;77: 1103–1107.PubMedGoogle Scholar
  35. 35.
    Schena Met al. Growth- and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells.Blood 1992;79: 2981–2989.PubMedGoogle Scholar
  36. 36.
    Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC. bcl-2 gene hypomethylation and high level expression in B-cell chronic lymphocytic leukemia.Blood 1993;82: 1820–1828.PubMedGoogle Scholar
  37. 37.
    Robertson LE, Plunkett W, McConnell K, Keating MJ, McDonnell TJ. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome.Leukemia 1996;10: 456–459.PubMedGoogle Scholar
  38. 38.
    McConkey DJet al. Apoptosis sensitivity in chronic lymphocytic leukemia is determined by endogenous endonuclease content and relative expression of BCL-2 and BAX.J Immunol 1996;156: 2624–2630.PubMedGoogle Scholar
  39. 39.
    Tangye SG, Raison RL. Leukaemic CD5+B-cell apoptosis: co-incidence of cell death and DNA fragmentation with reduced bcl-2 expression.Br J Haematol 1996;92: 950–953.PubMedCrossRefGoogle Scholar
  40. 40.
    Mapara MYet al. APO-1 mediated apoptosis or proliferation in human chronic B lymphocytic leukemia: correlation with bcl-2 oncogene expression.Eur J Immunol 1993;23: 702–708.PubMedCrossRefGoogle Scholar
  41. 41.
    Petersen AJet al. Nucleoside transporters, bcl-2 and apoptosis in CLL cells exposed to nucleoside analoguesin vitro.Eur J Haematol 1996;56: 213–220.PubMedCrossRefGoogle Scholar
  42. 42.
    König A, Schwartz GK, Mohammad RM, Al-Katib A, Gabrilove JL. The novel cyclin-dependent kinase inhibitor flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines.Blood 1997;90: 4307–4312.PubMedGoogle Scholar
  43. 43.
    Thomas Aet al. Drug-induced apoptosis in B-cell chronic lymphocytic leukemia: relationship between p53 gene mutation and bcl-2/bax proteins in drug resistance.Oncogene 1996;12: 1055–1062.PubMedGoogle Scholar
  44. 44.
    Pepper C, Bentley P, Hoy T. Regulation of clinical chemoresistance by bcl-2 and bax oncoproteins in B-cell chronic lymphocytic leukaemia.Br J Haematol 1996;95: 513–517.PubMedCrossRefGoogle Scholar
  45. 45.
    Robertson LE, Plunkett W, McConnell K, Keating MJ, McDonnell TJ. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome.Leukemia 1996;10: 456–459.PubMedGoogle Scholar
  46. 46.
    Christodoulopoulos Get al. Relationship between nitrogen mustard drug resistance in B-cell chronic lymphocytic leukemia (B-CLL) and protein expression of Bcl-2, Bax, Bcl-x and p53.Cancer Lett 1997;121: 59–67.PubMedCrossRefGoogle Scholar
  47. 47.
    Kitada Set al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses.Blood 1998;91: 3379–3389.PubMedGoogle Scholar
  48. 48.
    Nunez G, Merino R, Grillot D, Gonzalez-Garcia M. Bcl-2 and Bcl-x: regulatory switches for lymphoid death and survival.Immunol Today 1994;15: 582–587.PubMedCrossRefGoogle Scholar
  49. 49.
    Reed JC. Double identity for proteins of the Bcl-2 family.Nature 1997;387: 773–776.PubMedCrossRefGoogle Scholar
  50. 50.
    Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis.Nat Med 1997;3: 614–620.PubMedCrossRefGoogle Scholar
  51. 51.
    Osorio LM, Ordoñez C, Garcia CA, Jondal M, Chow SC. Evidence for protein tyrosine kinase involvement in CD6-induced T cell proliferation.Cell Immunol 1995;166: 44–52.PubMedCrossRefGoogle Scholar
  52. 52.
    Osorio LM, De Santiago A, Aguilar-Santelises M, Mellstedt H, Jondal M. CD6 ligation modulates the Bcl-2/Bax ratio and protects chronic lymphocytic leukemia B cells from apoptosis induced by anti-IgM.Blood 1997;89: 2833–2841.PubMedGoogle Scholar
  53. 53.
    Liu YJet al. Mechanism of antigen-driven selection in germinal centres.Nature 1989;342: 929–931.PubMedCrossRefGoogle Scholar
  54. 54.
    Durie FH, Foy TM, Masters SR, Laman JD, Noelle RJ. The role of CD40 in the regulation of humoral and cell-mediated immunity.Immunol Today 1994;15: 406–411.PubMedCrossRefGoogle Scholar
  55. 55.
    Liu YJ, Johnson GD, Gordon J, MacLennan IC. Germinal centres in T-cell-dependent antibody responses.Immunol Today 1992;13: 17–21.PubMedCrossRefGoogle Scholar
  56. 56.
    Lindhout E, Koopman G, Pals ST, de Groot C. Triple check for antigen specificity of B cells during germinal centre reactions.Immunol Today 1997;18: 573–577.PubMedCrossRefGoogle Scholar
  57. 57.
    Fluckiger ACet al. Responsiveness of chronic lymphocytic leukemia B cells activated via surface Igs or CD40 to B-cell tropic factors.Blood 1992;80: 3173–3181.PubMedGoogle Scholar
  58. 58.
    Buske Cet al. Stimulation of B-chronic lymphocytic leukemia cells by murine fibroblasts, IL-4, anti-CD40 antibodies, and the absolute CD40 ligand.Exp Hematol 1997;25: 329–237.PubMedGoogle Scholar
  59. 59.
    Wang D, Freeman GJ, Levine H, Ritz J, Robertson MJ. Role of the CD40 and CD95 (APO-1/Fas) antigens in the apoptosis of human B-cell malignancies.Br J Haematol 1997;97: 409–417.PubMedCrossRefGoogle Scholar
  60. 60.
    Romano MFet al. Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells.Blood 1998;92: 990–995.PubMedGoogle Scholar
  61. 61.
    Cantwell M, Hua T, Pappas J, Kipps TJ. Acquired CD40-ligand deficiency in chronic lymphocytic leukemia.Nat Med 1997;3: 984–989.PubMedCrossRefGoogle Scholar
  62. 62.
    Zhao Het al. B-cell chronic lymphocytic leukemia cells express a functional inducible nitric oxide synthase displaying anti-apoptotic activity.Blood 1998;92: 1031–1043.PubMedGoogle Scholar
  63. 63.
    Fournier Set al. The two CD23 isoforms display differential regulation in chronic lymphocytic leukaemia.Br J Haematol 1995;89: 373–379.PubMedGoogle Scholar
  64. 64.
    Zupo Set al. CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis.Blood 1996;88: 1365–1374.PubMedGoogle Scholar
  65. 65.
    Yonehara S, Ishii A, Yonehara M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor to tumor necrosis factor.J Exp Med 1989;169: 1747–1756.PubMedCrossRefGoogle Scholar
  66. 66.
    Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family.Cell 1993;75: 1169–1178.PubMedCrossRefGoogle Scholar
  67. 67.
    van Parijs L, Abbas AK. Role of Fas-mediated cell death in the regulation of immune responses.Curr Opin Immunol 1996;8: 355–361.PubMedCrossRefGoogle Scholar
  68. 68.
    Nagata S, Suda T. Fas and Fas ligand: lpr and gld mutations.Immunol Today 1995;16: 39–43.PubMedCrossRefGoogle Scholar
  69. 69.
    Adachi Met al. Enhanced and accelerated lymphoproliferation in Fas-null mice.Proc Natl Acad Sci USA 1996;93: 2131–2136.PubMedCrossRefGoogle Scholar
  70. 70.
    Panayiotidis P, Ganeshaguru K, Foroni L, Hoffbrand AV. Expression and function of the Fas antigen in B chronic lymphocytic leukemia and hairy cell leukemia.Leukemia 1995;9: 1227–1232.PubMedGoogle Scholar
  71. 71.
    Mainou-Fowler T, Craig VA, Copplestone AJ, Hamon MD, Prentice AG. Effect of anti-APO1 on spontaneous apoptosis of B cells in chronic lymphocytic leukaemia: the role of bcl-2 and interleukin 4.Leuk Lymphoma 1995;19: 301–308.PubMedCrossRefGoogle Scholar
  72. 72.
    Tinhofer Iet al. Differential sensitivity of CD4+ and CD8+ T lymphocytes to the killing efficacy of Fas (APO-1/CD95) ligand+ tumor cells in B chronic lymphocytic leukemia.Blood 1998;91: 4273–4281.PubMedGoogle Scholar
  73. 73.
    Osorio LMet al. Increased serum levels of soluble Fas correlate with B-CLL clinical progression. (submitted).Google Scholar
  74. 74.
    Knipping Eet al. Identification of soluble APO-1 in supernatants of human B- and T-cell lines and increased serum levels in B- and T-cell leukemias.Blood 1995;85: 1562–1569.PubMedGoogle Scholar
  75. 75.
    Cheng Jet al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule.Science 1994;263: 1759–1762.PubMedCrossRefGoogle Scholar
  76. 76.
    Papoff Get al. An N-terminal domain shared by Fas/Apo-1(CD95) soluble variants prevents cell deathin vitro.J Immunol 1996;156: 4622–4630.PubMedGoogle Scholar
  77. 77.
    Cascino I, Fiucci G, Papoff G, Ruberti G. Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing.J Immunol 1995;154: 2706–2713.PubMedGoogle Scholar
  78. 78.
    Hivroz C, Grillot-Courvalin C, Labaume S, Miglierina R, Claude-Brouet J. Cross-linking of membrane IgM on B-CLL cells: dissociation between intracellular free Ca2+ mobilization and cell proliferation.Eur J Immunol 1988;18: 1811–1817.PubMedCrossRefGoogle Scholar
  79. 79.
    Michel Fet al. Defective calcium response in B-chronic lymphocytic leukemia cells.J Immunol 1993;150: 3624–3633.PubMedGoogle Scholar
  80. 80.
    Bargou RCet al. Induction of Bax-α precedes apoptosis in a human B lymphoma cell line: potential role of the bcl-2 gene family in surface IgM-mediated apoptosis.Eur J Immunol 1995;25: 770–775.PubMedCrossRefGoogle Scholar
  81. 81.
    Knox KAet al. Second-messenger pathways involved in the regulation of survival in germinal-center B cells and in Burkitt lymphoma lines.Int J Cancer 1992;52: 959–966.PubMedCrossRefGoogle Scholar
  82. 82.
    Valentine MA, Licciardi KA. Rescue from anti-IgM-induced programmed cell death by the B cell surface proteins CD20 and CD40.Eur J Immunol 1992;22: 3141–3148.PubMedCrossRefGoogle Scholar
  83. 83.
    Weiss A, Littman DR. Signal transduction by lymphocyte antigen receptors.Cell 1994;76: 263–274.PubMedCrossRefGoogle Scholar

Copyright information

© Stockton Press 1998

Authors and Affiliations

  1. 1.Hematology Department, Center for Molecular MedicineKarolinska HospitalStockholmSweden

Personalised recommendations