Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Lymphoma

The isotype of the BCR as a surrogate for the GCB and ABC molecular subtypes in diffuse large B-cell lymphoma

Leukemia volume 25, pages 681–688 (2011)Cite this article

Subjects

Abstract

Gene expression profiling has identified two major molecular subtypes of diffuse large B-cell lymphoma (DLBCL) that are histologically indistinguishable but differ in cure rates. Here, we investigated whether the isotype of the B-cell receptor (BCR) expressed by the tumoral cells correlated with the molecular subtype and survival. Gene expression analysis clustered the 53 patients included in this study into three subgroups, 17 germinal center B-cell-like (GCB) cases, 26 activated B-cell-like (ABC) cases and 10 intermediate cases. The molecular subtype was correlated with the isotype, as 15/17 GCB cases expressed a secondary isotype (immunoglobulin (Ig)G or IgA), whereas 24/26 ABC cases expressed a primary isotype (IgM or IgD) (P<0.0001). There was a trend toward a worse outcome for patients with an ABC DLBCL and a shorter overall survival for patients with IgM+ tumor (P=0.21 and 0.014, respectively). Finally, fluorescence in situ hybridization (FISH) analysis revealed a striking asymmetric pattern, as the IGHM gene is conserved only on the productive IGH allele in most IgM+ tumors. Taken together, these data indicate that the isotype of the BCR is a reliable indicator for the GCB and ABC subtypes in DLBCL, and suggest that the conservation of an IgM is required for ABC DLBCL lymphomagenesis to occur.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–511.

    Article  CAS  Google Scholar 

  2. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103: 275–282.

    Article  CAS  Google Scholar 

  3. de Jong D, Rosenwald A, Chhanabhai M, Gaulard P, Klapper W, Lee A et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications—a study from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol 2007; 25: 805–812.

    Article  Google Scholar 

  4. Wright G, Tan B, Rosenwald A, Hurt EH, Wiestner A, Staudt LM . A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA 2003; 100: 9991–9996.

    Article  CAS  Google Scholar 

  5. Jais JP, Haioun C, Molina TJ, Rickman DS, de RA, Berger F et al. The expression of 16 genes related to the cell of origin and immune response predicts survival in elderly patients with diffuse large B-cell lymphoma treated with CHOP and rituximab. Leukemia 2008; 22: 1917–1924.

    Article  CAS  Google Scholar 

  6. Lenz G, Nagel I, Siebert R, Roschke AV, Sanger W, Wright GW et al. Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. J Exp Med 2007; 204: 633–643.

    Article  CAS  Google Scholar 

  7. Shaffer AL, Rosenwald A, Staudt LM . Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol 2002; 2: 920–932.

    Article  CAS  Google Scholar 

  8. Lossos IS, Levy R, Alizadeh AA . AID is expressed in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas and is not correlated with intraclonal heterogeneity. Leukemia 2004; 18: 1775–1779.

    Article  CAS  Google Scholar 

  9. van Dongen JJ, Langerak AW, Bruggemann M, Evans PA, Hummel M, Lavender FL et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003; 17: 2257–2317.

    Article  CAS  Google Scholar 

  10. Brochet X, Lefranc MP, Giudicelli V . IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V–J and V–D–J sequence analysis. Nucleic Acids Res 2008; 36: W503–W508.

    Article  CAS  Google Scholar 

  11. Lossos IS, Okada CY, Tibshirani R, Warnke R, Vose JM, Greiner TC et al. Molecular analysis of immunoglobulin genes in diffuse large B-cell lymphomas. Blood 2000; 95: 1797–1803.

    CAS  PubMed  Google Scholar 

  12. Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008; 359: 2313–2323.

    Article  CAS  Google Scholar 

  13. Nardini E, Rizzi S, Capello D, Vitolo U, Gaidano G, Menard S et al. Most immunoglobulin heavy chain switch mu rearrangements in B-cell chronic lymphocytic leukemia are internal deletions. FEBS Lett 2002; 518: 119–123.

    Article  CAS  Google Scholar 

  14. Vaandrager JW, Schuuring E, Kluin-Nelemans HC, Dyer MJ, Raap AK, Kluin PM . DNA fiber fluorescence in situ hybridization analysis of immunoglobulin class switching in B-cell neoplasia: aberrant CH gene rearrangements in follicle center-cell lymphoma. Blood 1998; 92: 2871–2878.

    CAS  PubMed  Google Scholar 

  15. Montesinos-Rongen M, Schmitz R, Courts C, Stenzel W, Bechtel D, Niedobitek G et al. Absence of immunoglobulin class switch in primary lymphomas of the central nervous system. Am J Pathol 2005; 166: 1773–1779.

    Article  CAS  Google Scholar 

  16. Miyazaki K, Yamaguchi M, Suguro M, Choi W, Ji Y, Xiao L et al. Gene expression profiling of diffuse large B-cell lymphoma supervised by CD21 expression. Br J Haematol 2008; 142: 562–570.

    Article  Google Scholar 

  17. Wilkins BS, Williamson JM, O’Brien CJ . Morphological and immunohistological study of testicular lymphomas. Histopathology 1989; 15: 147–156.

    Article  CAS  Google Scholar 

  18. Hoefnagel JJ, Dijkman R, Basso K, Jansen PM, Hallermann C, Willemze R et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood 2005; 105: 3671–3678.

    Article  CAS  Google Scholar 

  19. Koens L, Vermeer MH, Willemze R, Jansen PM . IgM expression on paraffin sections distinguishes primary cutaneous large B-cell lymphoma, leg type from primary cutaneous follicle center lymphoma. Am J Surg Pathol 2010; 34: 1043–1048.

    Article  Google Scholar 

  20. Booman M, Douwes J, Glas AM, de JD, Schuuring E, Kluin PM . Primary testicular diffuse large B-cell lymphomas have activated B-cell-like subtype characteristics. J Pathol 2006; 210: 163–171.

    Article  CAS  Google Scholar 

  21. Camilleri-Broet S, Criniere E, Broet P, Delwail V, Mokhtari K, Moreau A et al. A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood 2006; 107: 190–196.

    Article  CAS  Google Scholar 

  22. Hummel M, Berry JK, Dunnick W . Switch region content of hybridomas: the two spleen cell Igh loci tend to rearrange to the same isotype. J Immunol 1987; 138: 3539–3548.

    CAS  PubMed  Google Scholar 

  23. Radbruch A, Muller W, Rajewsky K . Class switch recombination is IgG1 specific on active and inactive IgH loci of IgG1-secreting B-cell blasts. Proc Natl Acad Sci USA 1986; 83: 3954–3957.

    Article  CAS  Google Scholar 

  24. Luby TM, Schrader CE, Stavnezer J, Selsing E . The mu switch region tandem repeats are important, but not required, for antibody class switch recombination. J Exp Med 2001; 193: 159–168.

    Article  CAS  Google Scholar 

  25. Khamlichi AA, Glaudet F, Oruc Z, Denis V, Le BM, Cogne M . Immunoglobulin class-switch recombination in mice devoid of any S mu tandem repeat. Blood 2004; 103: 3828–3836.

    Article  CAS  Google Scholar 

  26. Zhang T, Franklin A, Boboila C, McQuay A, Gallagher MP, Manis JP et al. Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM switch regions. Proc Natl Acad Sci USA 2010; 107: 3040–3045.

    Article  CAS  Google Scholar 

  27. Horikawa K, Martin SW, Pogue SL, Silver K, Peng K, Takatsu K et al. Enhancement and suppression of signaling by the conserved tail of IgG memory-type B cell antigen receptors. J Exp Med 2007; 204: 759–769.

    Article  CAS  Google Scholar 

  28. Sciammas R, Shaffer AL, Schatz JH, Zhao H, Staudt LM, Singh H . Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 2006; 25: 225–236.

    Article  CAS  Google Scholar 

  29. Staudt LM . Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol 2010; 2: a000109.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Ligue contre le Cancer (comité Seine Maritime), the ‘Agir avec Becquerel’ association, the GEFLUC association and the Institut National du Cancer (INCa, Grant no. PL070-2005, Professor T Fest, Rennes).

Author information

Authors and Affiliations

  1. INSERM U918, Laboratoire de génétique oncologique, Génétique et clinique des proliférations lymphoïdes, IFRMP23, Centre Henri Becquerel, Rouen, France

    P Ruminy, P Etancelin, L Couronné, F Parmentier, V Rainville, S Mareschal, E Bohers, C Burgot, M Cornic, P Bertrand, J-M Picquenot, F Jardin, H Tilly & C Bastard

  2. Laboratoire d’hématologie, CHU, Rouen, France

    B Lenormand

Authors
  1. P Ruminy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Etancelin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Couronné
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Parmentier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V Rainville
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Mareschal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E Bohers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Burgot
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Cornic
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P Bertrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. B Lenormand
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J-M Picquenot
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. F Jardin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. H Tilly
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. C Bastard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Ruminy.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruminy, P., Etancelin, P., Couronné, L. et al. The isotype of the BCR as a surrogate for the GCB and ABC molecular subtypes in diffuse large B-cell lymphoma. Leukemia 25, 681–688 (2011). https://doi.org/10.1038/leu.2010.302

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.302

Keywords

This article is cited by

Search

Advanced search

Quick links