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PMID: 15804279 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia.

Immunology ·Vol. 114 ·No. 4 ·2005-04-00 ·Pages 441-9

Packham G, Stevenson FK

Abstract

Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world and exists as subtypes with very different clinical courses. CLL is generally described as a disease of failed apoptosis. Apoptosis resistance may stem from a combination of microenvironmental survival signals as well as from intrinsic alterations in the apoptotic machinery within the CLL cell. The molecular mechanism involved in controlling apoptosis in CLL is complex and is influenced by many factors, including Bcl-2 family proteins, which are critical regulators of cell death. Here we review the significance of apoptosis dysregulation in CLL, focusing on the role of Bcl-2 and related Bcl-2 family proteins, such as Bax and Mcl-1. The differential properties of the newly described subsets of CLL are also highlighted.

MeSH Terms
Apoptosis/physiology B-Lymphocytes/physiology Humans Leukemia, Lymphocytic, Chronic, B-Cell/immunology,metabolism Myeloid Cell Leukemia Sequence 1 Protein Neoplasm Proteins/metabolism Proto-Oncogene Proteins c-bcl-2/metabolism Signal Transduction/physiology bcl-2-Associated X Protein
Chemicals
BAX protein, human Myeloid Cell Leukemia Sequence 1 Protein Neoplasm Proteins Proto-Oncogene Proteins c-bcl-2 bcl-2-Associated X Protein
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Packham Graham
Cancer Research UK Oncology Unit, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK. [email protected]
Stevenson Freda K
References (69)
69 references, click to expand
  1. Transgenic models of lymphoid neoplasia and development of a pan-hematopoietic vector.
    Oncogene. 1999 Sep 20;18(38):5268-77 PMID: 10498879
  2. In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia.
    Blood. 1999 Oct 15;94(8):2836-43 PMID: 10515887
  3. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia.
    Blood. 2005 Mar 1;105(5):2036-41 PMID: 15514014
  4. Antisense-mediated suppression of Bcl-2 highlights its pivotal role in failed apoptosis in B-cell chronic lymphocytic leukaemia.
    Br J Haematol. 1999 Dec;107(3):611-5 PMID: 10583267
  5. Mcl-1 deficiency results in peri-implantation embryonic lethality.
    Genes Dev. 2000 Jan 1;14(1):23-7 PMID: 10640272
  6. Peripheral blood CD38 expression predicts survival in B-cell chronic lymphocytic leukemia.
    Leuk Res. 2001 Nov;25(11):927-32 PMID: 11597727
  7. Survival of leukemic B cells promoted by engagement of the antigen receptor.
    Blood. 2001 Nov 15;98(10):3050-7 PMID: 11698290
  8. Bcl-2 antisense oligonucleotides enhance the cytotoxicity of chlorambucil in B-cell chronic lymphocytic leukaemia cells.
    Leuk Lymphoma. 2001 Jul;42(3):491-8 PMID: 11699414
  9. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells.
    J Exp Med. 2001 Dec 3;194(11):1625-38 PMID: 11733577
  10. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia.
    J Exp Med. 2001 Dec 3;194(11):1639-47 PMID: 11733578
  11. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease.
    Blood. 2002 Feb 1;99(3):1023-9 PMID: 11807008
  12. Involvement of protein kinase C and phosphatidylinositol 3-kinase pathways in the survival of B-cell chronic lymphocytic leukemia cells.
    Blood. 2002 Apr 15;99(8):2969-76 PMID: 11929788
  13. MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis.
    Leukemia. 2002 Apr;16(4):444-54 PMID: 11960321
  14. The protective effect of phorbol esters on Fas-mediated apoptosis in T cells. Transcriptional and postranscriptional regulation.
    Oncogene. 2002 Jul 25;21(32):4957-68 PMID: 12118374
  15. Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1.
    Blood. 2002 Sep 1;100(5):1795-801 PMID: 12176902
  16. Association of a novel single nucleotide polymorphism, G(-248)A, in the 5'-UTR of BAX gene in chronic lymphocytic leukemia with disease progression and treatment resistance.
    Cancer Lett. 2002 Dec 10;187(1-2):199-205 PMID: 12359369
  17. Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia.
    Oncogene. 2002 Oct 3;21(44):6809-18 PMID: 12360407
  18. Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome.
    Nature. 2002 Oct 10;419(6907):634-7 PMID: 12374983
  19. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cdelta.
    Blood. 2002 Nov 15;100(10):3741-8 PMID: 12393602
  20. Leukemic phase of B-cell lymphomas mimicking chronic lymphocytic leukemia and variants at presentation.
    Mod Pathol. 2002 Nov;15(11):1111-20 PMID: 12429788
  21. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia.
    Blood. 2002 Dec 15;100(13):4609-14 PMID: 12393534
  22. Antisense oligonucleotides complementary to Bax transcripts reduce the susceptibility of B-cell chronic lymphocytic leukaemia cells to apoptosis in a bcl-2 independent manner.
    Leuk Lymphoma. 2002 Oct;43(10):2003-9 PMID: 12481899
  23. Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia.
    Blood. 2003 Feb 1;101(3):1087-93 PMID: 12393552
  24. Role of apoptosis in the pathogenesis of B-cell chronic lymphocytic leukaemia.
    Br J Biomed Sci. 2002;59(4):235-8 PMID: 12572960
  25. B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor.
    Annu Rev Immunol. 2003;21:841-94 PMID: 12615894
  26. Bcl-2 and apoptosis in chronic lymphocytic leukemia.
    Curr Treat Options Oncol. 2003 Jun;4(3):211-8 PMID: 12718798
  27. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation.
    Genes Dev. 2003 Jun 15;17(12):1475-86 PMID: 12783855
  28. Bisindolylmaleimide IX is a potent inducer of apoptosis in chronic lymphocytic leukaemic cells and activates cleavage of Mcl-1.
    Leukemia. 2003 Oct;17(10):1981-9 PMID: 14513048
  29. The Bcl-2 family: roles in cell survival and oncogenesis.
    Oncogene. 2003 Nov 24;22(53):8590-607 PMID: 14634621
  30. DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells.
    Genes Dev. 2003 Dec 1;17(23):2922-32 PMID: 14633975
  31. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1.
    Nature. 2003 Dec 11;426(6967):671-6 PMID: 14668867
  32. Mcl-1 and Bcl-2/Bax ratio are associated with treatment response but not with Rai stage in B-cell chronic lymphocytic leukemia.
    Am J Hematol. 2004 Jan;75(1):22-33 PMID: 14695629
  33. Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway.
    Blood. 2004 Jan 15;103(2):679-88 PMID: 14504101
  34. Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations.
    Blood. 2004 Jan 15;103(2):375-82 PMID: 14504108
  35. The role of Bcl-2 family members in tumorigenesis.
    Biochim Biophys Acta. 2004 Mar 1;1644(2-3):229-49 PMID: 14996506
  36. Current strategies to target the anti-apoptotic Bcl-2 protein in cancer cells.
    Curr Med Chem. 2004 Apr;11(8):1031-9 PMID: 15083809
  37. Prognostic significance of a short sequence insertion in the MCL-1 promoter in chronic lymphocytic leukemia.
    J Natl Cancer Inst. 2004 May 5;96(9):673-82 PMID: 15126604
  38. Characterisation of Mcl-1 cleavage during apoptosis of haematopoietic cells.
    Br J Haematol. 2004 Jun;125(5):655-65 PMID: 15147382
  39. Chronic lymphocytic leukemia: revelations from the B-cell receptor.
    Blood. 2004 Jun 15;103(12):4389-95 PMID: 14962897
  40. Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage.
    Oncogene. 2004 Jun 17;23(28):4818-27 PMID: 15122313
  41. A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells.
    Leukemia. 2004 Aug;18(8):1391-400 PMID: 15175625
  42. The pathophysiology of mitochondrial cell death.
    Science. 2004 Jul 30;305(5684):626-9 PMID: 15286356
  43. Mcl-1.
    Int J Biochem Cell Biol. 2005 Feb;37(2):267-71 PMID: 15474972
  44. Spontaneous programmed death (apoptosis) of B-chronic lymphocytic leukaemia cells following their culture in vitro.
    Br J Haematol. 1989 Mar;71(3):343-50 PMID: 2930721
  45. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia.
    Blood. 1993 Sep 15;82(6):1820-8 PMID: 8104532
  46. Stimulation of germinal center B lymphocyte proliferation by an FDC-like cell line, HK.
    J Immunol. 1995 Aug 1;155(3):1101-9 PMID: 7543513
  47. Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro.
    Br J Haematol. 1996 Jan;92(1):97-103 PMID: 8562418
  48. Drug-induced apoptosis in B-cell chronic lymphocytic leukemia: relationship between p53 gene mutation and bcl-2/bax proteins in drug resistance.
    Oncogene. 1996 Mar 7;12(5):1055-62 PMID: 8649796
  49. CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis.
    Blood. 1996 Aug 15;88(4):1365-74 PMID: 8695855
  50. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis.
    Science. 1997 Feb 14;275(5302):983-6 PMID: 9020082
  51. Interleukin-4 prevents spontaneous in-vitro apoptosis in chronic lymphatic leukaemia but sensitizes B-CLL cells to melphalan cytotoxicity.
    Br J Haematol. 1997 Aug;98(2):413-7 PMID: 9266941
  52. The indispensable role of microenvironment in the natural history of low-grade B-cell neoplasms.
    Adv Cancer Res. 2000;79:157-73 PMID: 10818680
  53. In vivo localisation and stability of human Mcl-1 using green fluorescent protein (GFP) fusion proteins.
    FEBS Lett. 2000 Jul 28;478(1-2):72-6 PMID: 10922472
  54. Bcl-2/Bax ratios in chronic lymphocytic leukaemia and their correlation with in vitro apoptosis and clinical resistance.
    Br J Cancer. 1997;76(7):935-8 PMID: 9328155
  55. Unbalanced expression of bcl-2 family proteins in follicular lymphoma: contribution of CD40 signaling in promoting survival.
    Blood. 1998 Jan 1;91(1):244-51 PMID: 9414291
  56. Hematopoietic malignancies demonstrate loss-of-function mutations of BAX.
    Blood. 1998 Apr 15;91(8):2991-7 PMID: 9531611
  57. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses.
    Blood. 1998 May 1;91(9):3379-89 PMID: 9558396
  58. BAX frameshift mutations in cell lines derived from human haemopoietic malignancies are associated with resistance to apoptosis and microsatellite instability.
    Oncogene. 1998 Apr 9;16(14):1803-12 PMID: 9583678
  59. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1.
    Blood. 2000 Oct 15;96(8):2655-63 PMID: 11023495
  60. CD40 ligand in CLL pathogenesis and therapy.
    Leuk Lymphoma. 2000 May;37(5-6):461-72 PMID: 11042507
  61. Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia.
    Blood. 2001 May 1;97(9):2777-83 PMID: 11313271
  62. p53 dysfunction in B-cell chronic lymphocytic leukemia: inactivation of ATM as an alternative to TP53 mutation.
    Blood. 2001 Aug 1;98(3):814-22 PMID: 11468183
  63. Flavopiridol circumvents Bcl-2 family mediated inhibition of apoptosis and drug resistance in B-cell chronic lymphocytic leukaemia.
    Br J Haematol. 2001 Jul;114(1):70-7 PMID: 11472347
  64. Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells.
    Blood. 1998 Aug 1;92(3):990-5 PMID: 9680368
  65. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors.
    J Clin Invest. 1998 Oct 15;102(8):1515-25 PMID: 9788964
  66. Infrequent bax gene mutations in B-cell lymphomas.
    J Pathol. 1998 Dec;186(4):378-82 PMID: 10209486
  67. B-cell chronic lymphocytic leukemia: a bird of a different feather.
    J Clin Oncol. 1999 Jan;17(1):399-408 PMID: 10458259
  68. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.
    Blood. 1999 Sep 15;94(6):1840-7 PMID: 10477712
  69. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia.
    Blood. 1999 Sep 15;94(6):1848-54 PMID: 10477713
Article Info
Journal
Immunology
Abbr.
Immunology
ISSN
0019-2805
DOI
10.1111/j.1365-2567.2005.02117.x
Email
[email protected]
Published
2005-04-00
Pages
441-9
Language
English
Region
England
NLM ID
0374672
PMCID
PMC1782118
Subset
IM
External Links
PubMed source DOI: 10.1111/j.1365-2567.2005.02117.x PMC Full Text View journal details
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