Lymphoma pp 135-148 | Cite as

Stereotyped B Cell Receptors in B Cell Leukemias and Lymphomas

Part of the Methods in Molecular Biology book series (MIMB, volume 971)


Recent research has revealed the existence of subsets (clusters) of patients with different types of B-cell lymphomas and leukemias with restricted, “stereotyped” immunoglobulin (IG) variable heavy complementarity-determining region 3 (VH CDR3) sequences within their B cell receptors (BcR), suggesting selection by common epitopes or classes of structurally similar epitopes. BcR stereotypy was initially described in chronic lymphocytic leukemia (CLL), where it constitutes a remarkably frequent feature of the IG repertoire, and subsequently identified in other malignancies, including mantle cell lymphoma and splenic marginal-zone lymphoma. Of note, at least in CLL, emerging evidence indicates that the grouping of cases into distinct clusters with stereotyped BcR is functionally and prognostically relevant. Hence, the reliable identification of BcR stereotypy may assist in the investigation of the nature of the selecting antigens and immune pathways leading to lymphoma development, and also potentially pave the way for tailored treatment strategies applicable to each major stereotyped subset. In this chapter, we provide an overview of BcR stereotypy in human B-cell malignancies, and outline previous and current methodological approaches used for its identification.

Key words

B cell receptor Immunoglobulin gene CDR3 Antigen Pattern Stereotypy Bioinformatics 


  1. 1.
    Stevenson FK, Sahota SS, Ottensmeier CH, Zhu D, Forconi F, Hamblin TJ (2001) The occurrence and significance of V gene mutations in B cell-derived human malignancy. Adv Cancer Res 83:81–116PubMedCrossRefGoogle Scholar
  2. 2.
    Chiorazzi N, Ferrarini M (2003) B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor. Annu Rev Immunol 21:841–894PubMedCrossRefGoogle Scholar
  3. 3.
    Dunn-Walters D, Thiede C, Alpen B, Spencer J (2001) Somatic hypermutation and B-cell lymphoma. Philos Trans R Soc Lond B Biol Sci 356:73–82PubMedCrossRefGoogle Scholar
  4. 4.
    Ghia P, Granziero L, Chilosi M, Caligaris-Cappio F (2002) Chronic B cell malignancies and bone marrow microenvironment. Semin Cancer Biol 12:149–155PubMedCrossRefGoogle Scholar
  5. 5.
    O’Brien S, Burger J, Blum KA et al (2011) The Bruton’s Tyrosine Kinase (BTK) inhibitor PCI-32765 induces durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): follow-up of a phase Ib/II study. Blood 118 (Abstract 983)Google Scholar
  6. 6.
    Wang L, Martin P, Blum KA et al (2011) The Bruton’s Tyrosine Kinase inhibitor PCI-32765 is highly active as single-agent therapy in previously-treated mantle cell lymphoma (MCL): preliminary results of a phase II trial. Blood 118 (Abstract 442)Google Scholar
  7. 7.
    Chiorazzi N, Ferrarini M (2011) Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. Blood 117:1781–1791PubMedCrossRefGoogle Scholar
  8. 8.
    Schroeder HW Jr, Dighiero G (1994) The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunol Today 15:288–294PubMedCrossRefGoogle Scholar
  9. 9.
    Fais F, Ghiotto F, Hashimoto S et al (1998) Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest 102:1515–1525PubMedCrossRefGoogle Scholar
  10. 10.
    Stamatopoulos K, Belessi C, Hadzidimitriou A et al (2005) Immunoglobulin light chain repertoire in chronic lymphocytic leukemia. Blood 106:3575–3583PubMedCrossRefGoogle Scholar
  11. 11.
    Damle RN, Wasil T, Fais F et al (1999) Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840–1847PubMedGoogle Scholar
  12. 12.
    Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848–1854PubMedGoogle Scholar
  13. 13.
    Ghia P, Stamatopoulos K, Belessi C et al (2007) European Research Initiative on CLL. ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia. Leukemia 21:1–3PubMedCrossRefGoogle Scholar
  14. 14.
    Langerak AW, Davi F, Ghia P et al (2011) European Research Initiative on CLL (ERIC). Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases. Leukemia 25:979–984PubMedCrossRefGoogle Scholar
  15. 15.
    Hashimoto S, Dono M, Wakai M et al (1995) Somatic diversification and selection of immunoglobulin heavy and light chain variable region genes in IgG+ CD5+ chronic lymphocytic leukemia B cells. J Exp Med 181:1507–1517PubMedCrossRefGoogle Scholar
  16. 16.
    Efremov DG, Ivanovski M, Siljanovski N et al (1996) Restricted immunoglobulin VH region repertoire in chronic lymphocytic leukemia patients with autoimmune hemolytic anemia. Blood 87:3869–3876PubMedGoogle Scholar
  17. 17.
    Johnson TA, Rassenti LZ, Kipps TJ (1997) Ig VH1 genes expressed in B cell chronic lymphocytic leukemia exhibit distinctive molecular features. J Immunol 158:235–246PubMedGoogle Scholar
  18. 18.
    Widhopf GF 2nd, Kipps TJ (2001) Normal B cells express 51p1-encoded Ig heavy chains that are distinct from those expressed by chronic lymphocytic leukemia B cells. J Immunol 166:95–102PubMedGoogle Scholar
  19. 19.
    Tobin G, Thunberg U, Johnson A et al (2003) 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 101:4952–4957PubMedCrossRefGoogle Scholar
  20. 20.
    Widhopf GF 2nd, Rassenti LZ, Toy TL, Gribben JG, Wierda WG, Kipps TJ (2004) Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins. Blood 104:2499–2504PubMedCrossRefGoogle Scholar
  21. 21.
    Ghiotto F, Fais F, Valetto A et al (2004) Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia. J Clin Invest 113:1008–1016PubMedGoogle Scholar
  22. 22.
    Messmer BT, Albesiano E, Efremov DG et al (2004) Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med 200:519–525PubMedCrossRefGoogle Scholar
  23. 23.
    Tobin G, Thunberg U, Karlsson K et al (2004) Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia. Blood 104:2879–2885PubMedCrossRefGoogle Scholar
  24. 24.
    Stamatopoulos K, Belessi C, Moreno C et al (2007) Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations. Blood 109:259–270PubMedCrossRefGoogle Scholar
  25. 25.
    Murray F, Darzentas N, Hadzidimitriou A et al (2008) Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Blood 111:1524–1533PubMedCrossRefGoogle Scholar
  26. 26.
    Bomben R, Dal Bo M, Capello D et al (2009) Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study. Br J Haematol 144:492–506PubMedCrossRefGoogle Scholar
  27. 27.
    Darzentas N, Hadzidimitriou A, Murray F et al (2010) A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence. Leukemia 24:125–132PubMedCrossRefGoogle Scholar
  28. 28.
    Hadzidimitriou A, Agathangelidis A, Darzentas N et al (2011) Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood 118:3088–3095PubMedCrossRefGoogle Scholar
  29. 29.
    Agathangelidis A, Hadzidimitriou A, Rosenquist R, Stamatopoulos K (2011) Unlocking the secrets of immunoglobulin receptors in mantle cell lymphoma: implications for the origin and selection of the malignant cells. Semin Cancer Biol 21:299–307PubMedCrossRefGoogle Scholar
  30. 30.
    Bikos V, Darzentas N, Hadzidimitriou A et al (2012) Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications. Leukemia. 26:1638–1646]Google Scholar
  31. 31.
    Zibellini S, Capello D, Forconi F et al (2010) Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma. Haematologica 95:1792–1796PubMedCrossRefGoogle Scholar
  32. 32.
    Xu JL, Davis MM (2000) Diversity in the CDR3 region of V(H) is sufficient for most antibody specificities. Immunity 13:37–45PubMedCrossRefGoogle Scholar
  33. 33.
    Barrios Y, Jirholt P, Ohlin M (2004) Length of the antibody heavy chain complementarity determining region 3 as a specificity-determining factor. J Mol Recognit 17:332–338PubMedCrossRefGoogle Scholar
  34. 34.
    Henikoff S, Henikoff JG (1993) Performance evaluation of amino acid substitution matrices. Proteins 17:49–61PubMedCrossRefGoogle Scholar
  35. 35.
    Arvaniti E, Ntoufa S, Papakonstantinou N et al (2011) Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenetic significance in specific subsets of patients. Haematologica 96:1644–1652PubMedCrossRefGoogle Scholar
  36. 36.
    Kirkham PM, Mortari F, Newton JA, Schroeder HW Jr (1992) Immunoglobulin VH clan and family identity predicts variable domain structure and may influence antigen binding. EMBO J 11:603–609PubMedGoogle Scholar
  37. 37.
    Rigoutsos I, Floratos A (1998) Combinatorial pattern discovery in biological sequences: the TEIRESIAS algorithm. Bioinformatics 14:55–67PubMedCrossRefGoogle Scholar
  38. 38.
    Pommie C, Levadoux S, Sabatier R, Lefranc G, Lefranc MP (2004) IMGT standardized criteria for statistical analysis of immunoglobulin V-REGION amino acid properties. J Mol Recognit 17:17–32PubMedCrossRefGoogle Scholar
  39. 39.
    Agathangelidis A, Darzentas N, Hadzidimitriou A et al (2012) Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood 119:4467–4475Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  1. 1.Medical Genomics Research Group, Molecular Medicine Program, CEITEC/Central European Institute of TechnologyMasaryk UniversityBrnoCzech Republic
  2. 2.Hematology Department and HCT UnitG. Papanicolaou HospitalThessalonikiGreece
  3. 3.Institute of Agrobiotechnology, Center for Research and Technology HellasInstitute of Applied BiosciencesThessalonikiGreece

Personalised recommendations