B Cell Receptor and Antigens in CLL

  • Andreas Agathangelidis
  • Stavroula Ntoufa
  • Kostas StamatopoulosEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 792)


Nowadays, chronic lymphocytic leukemia (CLL) is considered as a prototypic antigen-driven lymphoma, with antigenic stimuli from the microenvironment promoting tumor outgrowth. Antigen recognition is a function of both the clonotypic B cell receptor immunoglobulin (BcR IG) and various other immune sensors, e.g., the Toll-like receptors. The critical role of BcR IG-mediated signaling in CLL development and evolution is underscored by the following: the disease-biased IG gene repertoire; the subdivision of CLL based on the somatic hypermutation load of the BcR IG into two broad categories with vastly different prognosis and eventual outcome; the existence of subsets of cases with distinct, quasi-identical (stereotyped) BcR IGs; and the clinical efficacy of novel therapeutics inhibiting BcR signaling. Here, we trace the immunogenetic evidence for antigen selection in CLL and also consider the types of implicated antigens as well as the immune signaling pathways relevant for CLL ontogeny and clonal progression.


B cell receptor Immunoglobulin Antigen Signaling VH CDR3 Somatic hypermutation 



We thank past and present members of our group for their commitment and enthusiasm. We also thank our fellow members in the IgCLL group, Drs. Belessi, Darzentas, Davi, Ghia, and Rosenquist, for our long-standing collaboration and stimulating scientific interaction.

This work was supported in part by the ENosAI project (code 09SYN-13-880) co-funded by the EU and the Hellenic General Secretariat for Research and Technology to KS; Cariplo Foundation (Milan, Italy) to KS.


  1. 1.
    Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352(8):804–15.PubMedGoogle Scholar
  2. 2.
    Chiorazzi N, Ferrarini M. Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. Blood. 2011;117(6):1781–91.PubMedGoogle Scholar
  3. 3.
    Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910–6.PubMedGoogle Scholar
  4. 4.
    Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G. B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011;118(16):4313–20.PubMedGoogle Scholar
  5. 5.
    Meeker TC, Grimaldi JC, O’Rourke R, Loeb J, Juliusson G, Einhorn S. Lack of detectable somatic hypermutation in the V region of the Ig H chain gene of a human chronic B lymphocytic leukemia. J Immunol. 1988;141(11):3994–8.PubMedGoogle Scholar
  6. 6.
    Kuppers R, Gause A, Rajewsky K. B cells of chronic lymphatic leukemia express V genes in unmutated form. Leuk Res. 1991;15(6):487–96.PubMedGoogle Scholar
  7. 7.
    Friedman DF, Moore JS, Erikson J, Manz J, Goldman J, Nowell PC, et al. Variable region gene analysis of an isotype-switched (IgA) variant of chronic lymphocytic leukemia. Blood. 1992;80(9):2287–97.PubMedGoogle Scholar
  8. 8.
    Cai J, Humphries C, Richardson A, Tucker PW. Extensive and selective mutation of a rearranged VH5 gene in human B cell chronic lymphocytic leukemia. J Exp Med. 1992;176(4):1073–81.PubMedGoogle Scholar
  9. 9.
    Hashimoto S, Wakai M, Silver J, Chiorazzi N. Biased usage of variable and constant-region Ig genes by IgG+, CD5+ human leukemic B cells. Ann N Y Acad Sci. 1992;651:477–9.PubMedGoogle Scholar
  10. 10.
    Ebeling SB, Schutte ME, Logtenberg T. Molecular analysis of VH and VL regions expressed in IgG-bearing chronic lymphocytic leukemia (CLL): further evidence that CLL is a heterogeneous group of tumors. Blood. 1993;82(5):1626–31.PubMedGoogle Scholar
  11. 11.
    Fais F, Ghiotto F, Hashimoto S, Sellars B, Valetto A, Allen SL, et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest. 1998;102(8):1515–25.PubMedGoogle Scholar
  12. 12.
    Messmer BT, Albesiano E, Efremov DG, Ghiotto F, Allen SL, Kolitz J, et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med. 2004;200(4):519–25.PubMedGoogle Scholar
  13. 13.
    Widhopf 2nd GF, Rassenti LZ, Toy TL, Gribben JG, Wierda WG, Kipps TJ. Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins. Blood. 2004;104(8):2499–504.PubMedGoogle Scholar
  14. 14.
    Tobin G, Thunberg U, Karlsson K, Murray F, Laurell A, Willander K, et al. Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia. Blood. 2004;104(9):2879–85.PubMedGoogle Scholar
  15. 15.
    Stamatopoulos K, Belessi C, Moreno C, Boudjograh M, Guida G, Smilevska T, et al. Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations. Blood. 2007;109(1):259–70.PubMedGoogle Scholar
  16. 16.
    Murray F, Darzentas N, Hadzidimitriou A, Tobin G, Boudjogra M, Scielzo C, et al. Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Blood. 2008;111(3):1524–33.PubMedGoogle Scholar
  17. 17.
    Bomben R, Dal Bo M, Capello D, Forconi F, Maffei R, Laurenti L, et al. Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study. Br J Haematol. 2009;144(4):492–506.PubMedGoogle Scholar
  18. 18.
    Agathangelidis A, Darzentas N, Hadzidimitriou A, Brochet X, Murray F, Yan XJ, et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood. 2012;119(19):4467–75.PubMedGoogle Scholar
  19. 19.
    Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94(6):1840–7.PubMedGoogle Scholar
  20. 20.
    Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848–54.PubMedGoogle Scholar
  21. 21.
    Forconi F, Sahota SS, Lauria F, Stevenson FK. Revisiting the definition of somatic mutational status in B-cell tumors: does 98% homology mean that a V(H)-gene is unmutated? Leukemia. 2004;18(4):882–3.PubMedGoogle Scholar
  22. 22.
    Barbas SM, Ditzel HJ, Salonen EM, Yang WP, Silverman GJ, Burton DR. Human autoantibody recognition of DNA. Proc Natl Acad Sci U S A. 1995;92(7):2529–33.PubMedGoogle Scholar
  23. 23.
    Rahman A, Giles I, Haley J, Isenberg D. Systematic analysis of sequences of anti-DNA antibodies–relevance to theories of origin and pathogenicity. Lupus. 2002;11(12):807–23.PubMedGoogle Scholar
  24. 24.
    Hamblin TJ, Davis ZA, Oscier DG. Determination of how many immunoglobulin variable region heavy chain mutations are allowable in unmutated chronic lymphocytic leukaemia—long-term follow up of patients with different percentages of mutations. Br J Haematol. 2008;140(3):320–3.PubMedGoogle Scholar
  25. 25.
    Tobin G, Thunberg U, Johnson A, Thorn I, Soderberg O, Hultdin M, et al. Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood. 2002;99(6):2262–4.PubMedGoogle Scholar
  26. 26.
    Ghia P, Stamatopoulos K, Belessi C, Moreno C, Stella S, Guida G, et al. Geographic patterns and pathogenetic implications of IGHV gene usage in chronic lymphocytic leukemia: the lesson of the IGHV3-21 gene. Blood. 2005;105(4):1678–85.PubMedGoogle Scholar
  27. 27.
    Bomben R, Dal-Bo M, Benedetti D, Capello D, Forconi F, Marconi D, et al. Expression of mutated IGHV3-23 genes in chronic lymphocytic leukemia identifies a disease subset with peculiar clinical and biological features. Clin Cancer Res. 2010;16(2):620–8.PubMedGoogle Scholar
  28. 28.
    Del Giudice I, Chiaretti S, Tavolaro S, De Propris MS, Maggio R, Mancini F, et al. Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood. 2009;114(3):638–46.PubMedGoogle Scholar
  29. 29.
    Capello D, Zucchetto A, Degan M, Bomben R, Dal Bo M, Efremov DG, et al. Immunophenotypic characterization of IgVH3-72 B-cell chronic lymphocytic leukaemia (B-CLL). Leuk Res. 2006;30(9):1197–9.PubMedGoogle Scholar
  30. 30.
    Matthews C, Catherwood MA, Morris TC, Alexander HD. V(H)3-48 and V(H)3-53, as well as V(H)3-21, gene rearrangements define unique subgroups in CLL and are associated with biased lambda light chain restriction, homologous LCDR3 sequences and poor prognosis. Leuk Res. 2007;31(2):231–4.PubMedGoogle Scholar
  31. 31.
    Hashimoto S, Dono M, Wakai M, Allen SL, Lichtman SM, Schulman P, et al. Somatic diversification and selection of immunoglobulin heavy and light chain variable region genes in IgG+ CD5+ chronic lymphocytic leukemia B cells. J Exp Med. 1995;181(4):1507–17.PubMedGoogle Scholar
  32. 32.
    Kipps TJ. Immunoglobulin genes in chronic lymphocytic leukemia. Blood Cells. 1993;19(3):615–25. discussion 31–2.PubMedGoogle Scholar
  33. 33.
    Tobin G, Thunberg U, Johnson A, Eriksson I, Soderberg O, Karlsson K, et al. Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted Vlambda2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope. Blood. 2003;101(12):4952–7.PubMedGoogle Scholar
  34. 34.
    Ghiotto F, Fais F, Valetto A, Albesiano E, Hashimoto S, Dono M, et al. Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia. J Clin Invest. 2004;113(7):1008–16.PubMedGoogle Scholar
  35. 35.
    Darzentas N, Hadzidimitriou A, Murray F, Hatzi K, Josefsson P, Laoutaris N, et al. A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence. Leukemia. 2010;24(1):125–32.PubMedGoogle Scholar
  36. 36.
    Belessi CJ, Davi FB, Stamatopoulos KE, Degano M, Andreou TM, Moreno C, et al. IGHV gene insertions and deletions in chronic lymphocytic leukemia: “CLL-biased” deletions in a subset of cases with stereotyped receptors. Eur J Immunol. 2006;36(7):1963–74.PubMedGoogle Scholar
  37. 37.
    Wilson PC, de Bouteiller O, Liu YJ, Potter K, Banchereau J, Capra JD, et al. Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes. J Exp Med. 1998;187(1):59–70.PubMedGoogle Scholar
  38. 38.
    Klein U, Goossens T, Fischer M, Kanzler H, Braeuninger A, Rajewsky K, et al. Somatic hypermutation in normal and transformed human B cells. Immunol Rev. 1998;162:261–80.PubMedGoogle Scholar
  39. 39.
    Kuppers R. Somatic hypermutation and B cell receptor selection in normal and transformed human B cells. Ann N Y Acad Sci. 2003;987:173–9.PubMedGoogle Scholar
  40. 40.
    Kienle D, Krober A, Katzenberger T, Ott G, Leupolt E, Barth TF, et al. VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome. Blood. 2003;102(8):3003–9.PubMedGoogle Scholar
  41. 41.
    Camacho FI, Algara P, Rodriguez A, Ruiz-Ballesteros E, Mollejo M, Martinez N, et al. Molecular heterogeneity in MCL defined by the use of specific VH genes and the frequency of somatic mutations. Blood. 2003;101(10):4042–6.PubMedGoogle Scholar
  42. 42.
    Orchard J, Garand R, Davis Z, Babbage G, Sahota S, Matutes E, et al. A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease. Blood. 2003;101(12):4975–81.PubMedGoogle Scholar
  43. 43.
    Schraders M, Oeschger S, Kluin PM, Hebeda K, Schuuring E, Groenen PJ, et al. Hypermutation in mantle cell lymphoma does not indicate a clinical or biological subentity. Mod Pathol. 2009;22(3):416–25.PubMedGoogle Scholar
  44. 44.
    Thorselius M, Walsh S, Eriksson I, Thunberg U, Johnson A, Backlin C, et al. Somatic hypermutation and V(H) gene usage in mantle cell lymphoma. Eur J Haematol. 2002;68(4):217–24.PubMedGoogle Scholar
  45. 45.
    Walsh SH, Thorselius M, Johnson A, Soderberg O, Jerkeman M, Bjorck E, et al. Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma. Blood. 2003;101(10):4047–54.PubMedGoogle Scholar
  46. 46.
    Papadaki T, Stamatopoulos K, Belessi C, Pouliou E, Parasi A, Douka V, et al. Splenic marginal-zone lymphoma: one or more entities? A histologic, immunohistochemical, and molecular study of 42 cases. Am J Surg Pathol. 2007;31(3):438–46.PubMedGoogle Scholar
  47. 47.
    Stamatopoulos K, Belessi C, Papadaki T, Kalagiakou E, Stavroyianni N, Douka V, et al. Immunoglobulin heavy- and light-chain repertoire in splenic marginal zone lymphoma. Mol Med. 2004;10(7–12):89–95.PubMedGoogle Scholar
  48. 48.
    Hockley SL, Giannouli S, Morilla A, Wotherspoon A, Morgan GJ, Matutes E, et al. Insight into the molecular pathogenesis of hairy cell leukaemia, hairy cell leukaemia variant and splenic marginal zone lymphoma, provided by the analysis of their IGH rearrangements and somatic hypermutation patterns. Br J Haematol. 2010;148(4):666–9.PubMedGoogle Scholar
  49. 49.
    Zhu D, Orchard J, Oscier DG, Wright DH, Stevenson FK. V(H) gene analysis of splenic marginal zone lymphomas reveals diversity in mutational status and initiation of somatic mutation in vivo. Blood. 2002;100(7):2659–61.PubMedGoogle Scholar
  50. 50.
    Hadzidimitriou A, Agathangelidis A, Darzentas N, Murray F, Delfau-Larue MH, Pedersen LB, et al. Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood. 2011;118(11):3088–95.PubMedGoogle Scholar
  51. 51.
    Zibellini S, Capello D, Forconi F, Marcatili P, Rossi D, Rattotti S, et al. Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma. Haematologica. 2010;95(10):1792–6.PubMedGoogle Scholar
  52. 52.
    Bikos V, Darzentas N, Hadzidimitriou A, Davis Z, Hockley S, Traverse-Glehen A, et al. Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications. Leukemia. 2012;26(7):1638–46.PubMedGoogle Scholar
  53. 53.
    Visco C, Maura F, Tuana G, Agnelli L, Lionetti M, Fabris S, et al. Immune thrombocytopenia in patients with chronic lymphocytic leukemia is associated with stereotyped B-cell receptors. Clin Cancer Res. 2012;18(7):1870–8.PubMedGoogle Scholar
  54. 54.
    Maura F, Cutrona G, Fabris S, Colombo M, Tuana G, Agnelli L, et al. Relevance of stereotyped B-cell receptors in the context of the molecular, cytogenetic and clinical features of chronic lymphocytic leukemia. PLoS One. 2011;6(8):e24313.PubMedGoogle Scholar
  55. 55.
    Marincevic M, Cahill N, Gunnarsson R, Isaksson A, Mansouri M, Goransson H, et al. High-density screening reveals a different spectrum of genomic aberrations in chronic lymphocytic leukemia patients with ‘stereotyped’ IGHV3-21 and IGHV4-34 B-cell receptors. Haematologica. 2010;95(9):1519–25.PubMedGoogle Scholar
  56. 56.
    Falt S, Merup M, Tobin G, Thunberg U, Gahrton G, Rosenquist R, et al. Distinctive gene expression pattern in VH3-21 utilizing B-cell chronic lymphocytic leukemia. Blood. 2005;106(2):681–9.PubMedGoogle Scholar
  57. 57.
    Rossi D, Spina V, Cerri M, Rasi S, Deambrogi C, De Paoli L, et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res. 2009;15(13):4415–22.PubMedGoogle Scholar
  58. 58.
    Chapiro E, Radford-Weiss I, Bastard C, Luquet I, Lefebvre C, Callet-Bauchu E, et al. The most frequent t(14;19)(q32;q13)-positive B-cell malignancy corresponds to an aggressive subgroup of atypical chronic lymphocytic leukemia. Leukemia. 2008;22(11):2123–7.PubMedGoogle Scholar
  59. 59.
    Marincevic M, Mansouri M, Kanduri M, Isaksson A, Goransson H, Smedby KE, et al. Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors. Haematologica. 2010;95(12):2072–9.PubMedGoogle Scholar
  60. 60.
    Damle RN, Ghiotto F, Valetto A, Albesiano E, Fais F, Yan XJ, et al. B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes. Blood. 2002;99(11):4087–93.PubMedGoogle Scholar
  61. 61.
    Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med. 2001;194(11):1625–38.PubMedGoogle Scholar
  62. 62.
    Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med. 2001;194(11):1639–47.PubMedGoogle Scholar
  63. 63.
    Arvaniti E, Ntoufa S, Papakonstantinou N, Touloumenidou T, Laoutaris N, Anagnostopoulos A, et al. Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients. Haematologica. 2011;96(11):1644–52.PubMedGoogle Scholar
  64. 64.
    Broker BM, Klajman A, Youinou P, Jouquan J, Worman CP, Murphy J, et al. Chronic lymphocytic leukemic (CLL) cells secrete multispecific autoantibodies. J Autoimmun. 1988;1(5):469–81.PubMedGoogle Scholar
  65. 65.
    Sthoeger ZM, Wakai M, Tse DB, Vinciguerra VP, Allen SL, Budman DR, et al. Production of autoantibodies by CD5-expressing B lymphocytes from patients with chronic lymphocytic leukemia. J Exp Med. 1989;169(1):255–68.PubMedGoogle Scholar
  66. 66.
    Herve M, Xu K, Ng YS, Wardemann H, Albesiano E, Messmer BT, et al. Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J Clin Invest. 2005;115(6):1636–43.PubMedGoogle Scholar
  67. 67.
    Lanemo Myhrinder A, Hellqvist E, Sidorova E, Soderberg A, Baxendale H, Dahle C, et al. A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies. Blood. 2008;111(7):3838–48.PubMedGoogle Scholar
  68. 68.
    Fu M, Fan PS, Li W, Li CX, Xing Y, An JG, et al. Identification of poly-reactive natural IgM antibody that recognizes late apoptotic cells and promotes phagocytosis of the cells. Apoptosis. 2007;12(2):355–62.PubMedGoogle Scholar
  69. 69.
    Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med. 1994;179(4):1317–30.PubMedGoogle Scholar
  70. 70.
    Carroll MC. A protective role for innate immunity in systemic lupus erythematosus. Nat Rev Immunol. 2004;4(10):825–31.PubMedGoogle Scholar
  71. 71.
    Landgren O, Rapkin JS, Caporaso NE, Mellemkjaer L, Gridley G, Goldin LR, et al. Respiratory tract infections and subsequent risk of chronic lymphocytic leukemia. Blood. 2007;109(5):2198–201.PubMedGoogle Scholar
  72. 72.
    Steininger C, Rassenti LZ, Vanura K, Eigenberger K, Jager U, Kipps TJ, et al. Relative seroprevalence of human herpes viruses in patients with chronic lymphocytic leukaemia. Eur J Clin Invest. 2009;39(6):497–506.PubMedGoogle Scholar
  73. 73.
    Steininger C, Widhopf 2nd GF, Ghia EM, Morello CS, Vanura K, Sanders R, et al. Recombinant antibodies encoded by IGHV1-69 react with pUL32, a phosphoprotein of cytomegalovirus and B-cell superantigen. Blood. 2012;119(10):2293–301.PubMedGoogle Scholar
  74. 74.
    Silberstein LE, George A, Durdik JM, Kipps TJ. The V4-34 encoded anti-i autoantibodies recognize a large subset of human and mouse B-cells. Blood Cells Mol Dis. 1996;22(2):126–38.PubMedGoogle Scholar
  75. 75.
    Mockridge CI, Rahman A, Buchan S, Hamblin T, Isenberg DA, Stevenson FK, et al. Common patterns of B cell perturbation and expanded V4-34 immunoglobulin gene usage in autoimmunity and infection. Autoimmunity. 2004;37(1):9–15.PubMedGoogle Scholar
  76. 76.
    Kostareli E, Hadzidimitriou A, Stavroyianni N, Darzentas N, Athanasiadou A, Gounari M, et al. Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors. Leukemia. 2009;23(5):919–24.PubMedGoogle Scholar
  77. 77.
    Sutton LA, Kostareli E, Hadzidimitriou A, Darzentas N, Tsaftaris A, Anagnostopoulos A, et al. Extensive intraclonal diversification in a subgroup of chronic lymphocytic leukemia patients with stereotyped IGHV4-34 receptors: implications for ongoing interactions with antigen. Blood. 2009;114(20):4460–8.PubMedGoogle Scholar
  78. 78.
    Kostareli E, Sutton LA, Hadzidimitriou A, Darzentas N, Kouvatsi A, Tsaftaris A, et al. Intraclonal diversification of immunoglobulin light chains in a subset of chronic lymphocytic leukemia alludes to antigen-driven clonal evolution. Leukemia. 2010;24(7):1317–24.PubMedGoogle Scholar
  79. 79.
    Kostareli E, Gounari M, Janus A, Murray F, Brochet X, Giudicelli V, et al. Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity. Leukemia. 2012;26(5):1127–31.PubMedGoogle Scholar
  80. 80.
    Chu CC, Catera R, Hatzi K, Yan XJ, Zhang L, Wang XB, et al. Chronic lymphocytic leukemia antibodies with a common stereotypic rearrangement recognize nonmuscle myosin heavy chain IIA. Blood. 2008;112(13):5122–9.PubMedGoogle Scholar
  81. 81.
    Chu CC, Catera R, Zhang L, Didier S, Agagnina BM, Damle RN, et al. Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. Blood. 2010;115(19):3907–15.PubMedGoogle Scholar
  82. 82.
    Dal Porto JM, Gauld SB, Merrell KT, Mills D, Pugh-Bernard AE, Cambier J. B cell antigen receptor signaling 101. Mol Immunol. 2004;41(6–7):599–613.PubMedGoogle Scholar
  83. 83.
    Muzio M, Apollonio B, Scielzo C, Frenquelli M, Vandoni I, Boussiotis V, et al. Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy. Blood. 2008;112(1):188–95.PubMedGoogle Scholar
  84. 84.
    Hivroz C, Geny B, Brouet JC, Grillot-Courvalin C. Altered signal transduction secondary to surface IgM cross-linking on B-chronic lymphocytic leukemia cells. Differential activation of the phosphatidylinositol-specific phospholipase C. J Immunol. 1990;144(6):2351–8.PubMedGoogle Scholar
  85. 85.
    Semichon M, Merle-Beral H, Lang V, Bismuth G. Normal Syk protein level but abnormal tyrosine phosphorylation in B-CLL cells. Leukemia. 1997;11(11):1921–8.PubMedGoogle Scholar
  86. 86.
    Mockridge CI, Potter KN, Wheatley I, Neville LA, Packham G, Stevenson FK. Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status. Blood. 2007;109(10):4424–31.PubMedGoogle Scholar
  87. 87.
    Yarkoni Y, Getahun A, Cambier JC. Molecular underpinning of B-cell anergy. Immunol Rev. 2010;237(1):249–63.PubMedGoogle Scholar
  88. 88.
    Duty JA, Szodoray P, Zheng NY, Koelsch KA, Zhang Q, Swiatkowski M, et al. Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors. J Exp Med. 2009;206(1):139–51.PubMedGoogle Scholar
  89. 89.
    Taylor JJ, Martinez RJ, Titcombe PJ, Barsness LO, Thomas SR, Zhang N, et al. Deletion and anergy of polyclonal B cells specific for ubiquitous membrane-bound self-antigen. J Exp Med. 2012;209(11):2065–77.PubMedGoogle Scholar
  90. 90.
    Lanham S, Hamblin T, Oscier D, Ibbotson R, Stevenson F, Packham G. Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. Blood. 2003;101(3):1087–93.PubMedGoogle Scholar
  91. 91.
    Petlickovski A, Laurenti L, Li X, Marietti S, Chiusolo P, Sica S, et al. Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. Blood. 2005;105(12):4820–7.PubMedGoogle Scholar
  92. 92.
    Deglesne PA, Chevallier N, Letestu R, Baran-Marszak F, Beitar T, Salanoubat C, et al. Survival response to B-cell receptor ligation is restricted to progressive chronic lymphocytic leukemia cells irrespective of Zap70 expression. Cancer Res. 2006;66(14):7158–66.PubMedGoogle Scholar
  93. 93.
    Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675–80.PubMedGoogle Scholar
  94. 94.
    Kawai T, Akira S. Pathogen recognition with Toll-like receptors. Curr Opin Immunol. 2005;17(4):338–44.PubMedGoogle Scholar
  95. 95.
    Meyer-Bahlburg A, Khim S, Rawlings DJ. B cell intrinsic TLR signals amplify but are not required for humoral immunity. J Exp Med. 2007;204(13):3095–101.PubMedGoogle Scholar
  96. 96.
    Ruprecht CR, Lanzavecchia A. Toll-like receptor stimulation as a third signal required for activation of human naive B cells. Eur J Immunol. 2006;36(4):810–6.PubMedGoogle Scholar
  97. 97.
    Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002;416(6881):603–7.PubMedGoogle Scholar
  98. 98.
    Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, Mamula MJ, et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med. 2005;202(9):1171–7.PubMedGoogle Scholar
  99. 99.
    Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity. 2006;25(3):417–28.PubMedGoogle Scholar
  100. 100.
    Rui L, Vinuesa CG, Blasioli J, Goodnow CC. Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling. Nat Immunol. 2003;4(6):594–600.PubMedGoogle Scholar
  101. 101.
    Jahrsdorfer B, Wooldridge JE, Blackwell SE, Taylor CM, Griffith TS, Link BK, et al. Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells. J Leukoc Biol. 2005;77(3):378–87.PubMedGoogle Scholar
  102. 102.
    Decker T, Schneller F, Sparwasser T, Tretter T, Lipford GB, Wagner H, et al. Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells. Blood. 2000;95(3):999–1006.PubMedGoogle Scholar
  103. 103.
    Spaner DE, Shi Y, White D, Mena J, Hammond C, Tomic J, et al. Immunomodulatory effects of Toll-like receptor-7 activation on CLL cells. Leukemia. 2006;20(2):286–95.PubMedGoogle Scholar
  104. 104.
    Shi Y, White D, He L, Miller RL, Spaner DE. Toll-like receptor-7 tolerizes malignant B cells and enhances killing by cytotoxic agents. Cancer Res. 2007;67(4):1823–31.PubMedGoogle Scholar
  105. 105.
    Hammadi A, Billard C, Faussat AM, Kolb JP. Resistance in B-cell chronic lymphocytic leukemia (B-CLL) cells through engagement of Toll-like receptor 7 (TLR-7) and NF-κB activation. Nitric Oxide. 2008;19:138–45.PubMedGoogle Scholar
  106. 106.
    Ntoufa S, Vardi A, Papakonstantinou N, Anagnostopoulos A, Aleporou-Marinou V, Belessi C, et al. Distinct innate immunity pathways to activation and tolerance in subgroups of chronic lymphocytic leukemia with distinct immunoglobulin receptors. Mol Med. 2012;18:1281–91.PubMedGoogle Scholar
  107. 107.
    Wiestner A. Emerging role of kinase targeted strategies in chronic lymphocytic leukemia. Blood. 2012;120(24):4684–91.PubMedGoogle Scholar
  108. 108.
    Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120(6):1175–84.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Andreas Agathangelidis
    • 1
  • Stavroula Ntoufa
    • 2
    • 3
  • Kostas Stamatopoulos
    • 2
    • 3
    Email author
  1. 1.B Cell Neoplasia UnitIstituto Scientifico San RaffaeleMilanItaly
  2. 2.Hematology Department and HCT UnitG. Papanicolaou HospitalThessalonikiGreece
  3. 3.Institute of Applied BiosciencesCenter for Research and Technology HellasThessalonikiGreece

Personalised recommendations