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Lymphoma

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

Leukemia volume 26, pages 1638–1646 (2012)Cite this article

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Abstract

We performed an immunogenetic analysis of 345 IGHV–IGHD–IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele *04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2*04 peaked at 31%. The IGHV1-2*04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2*04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97–99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2*04 allele.

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Acknowledgements

We express our gratitude to Professor Marie-Paule Lefranc (Laboratoire d’Immunogenetique Moleculaire, LIGM, Universite Montpellier II, Montpellier, France) for valuable support, suggestions and guidance in immunoglobulin gene sequence analysis. The analysis of French cases was supported by grants from the Comité du Rhône de la Ligue Nationale contre le Cancer. The analysis of the Spanish cases was supported by grants from the AECC and the Ministerio de Ciencia e Innovación, Spain (SAF2008-03871, RETICS). The analysis of cases from the Institute of Cancer Research (London, UK) was supported by the UK Cancer Research Fund. The antibody molecular dynamics simulation was supported by a research grant from the Italian Ministry for University and Research (FIRB) and the CARIPLO Foundation, Milano, Italy.

Author Contributions

Vasilis Bikos performed research, analyzed data and wrote the paper. Nikos Darzentas and Anastasia Hadzidimitriou performed research and analyzed data. Zadie Davis, Sarah Hockley, Alexandra Traverse-Glehen, Patricia Algara, Alessandra Santoro, David Gonzalez, Manuela Mollejo, Antonis Dagklis and Pascale Felman performed research. George Bourikas, Achilles Anagnostopoulos and Athanasios Tsaftaris supervised research. Fabrizio Gangemi and Massimo Degano performed the antibody molecular dynamics simulation. Emilio Iannitto, Maurilio Ponzoni, Francoise Berger, Chrysoula Belessi, Paolo Ghia, Theodora Papadaki, Ahmet Dogan, Estella Matutes, Miguel Angel Piris and David Oscier provided samples and associated clinicopathological data, and supervised research. Kostas Stamatopoulos designed the study, supervised research and wrote the paper.

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Authors and Affiliations

  1. Democritus University of Thrace, Alexandroupolis, Greece

    V Bikos & G Bourikas

  2. Institute of Agrobiotechnology, Center for Research and Technology Hellas, Thessaloniki, Greece

    N Darzentas, A Hadzidimitriou, A Tsaftaris & K Stamatopoulos

  3. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    Z Davis & D Oscier

  4. Section of Haemato-Oncology, Institute of Cancer Research, London, UK

    S Hockley, D Gonzalez & E Matutes

  5. Department of Pathology, Hospices Civils de Lyon, Université Lyon 1, Lyon, France

    A Traverse-Glehen & F Berger

  6. Hospital Virgen de la Salud, Toledo, Spain

    P Algara & M Mollejo

  7. Laboratory of Hematology, Villa Sofia-Cervello Hospital, Palermo, Italy

    A Santoro

  8. Unit of Lymphoid Malignancies and MAGIC (Microenvironment and Genes in Cancers of the blood) Interdivisional Research Program, Laboratory of B cell Neoplasia, Università Vita-Salute San Raffaele and Istituto Scientifico San Raffaele, Milan, Italy

    A Dagklis & P Ghia

  9. Division of Immunology, Biocrystallography Unit, Transplantation, and Infectious Diseases, Scientific Institute San Raffaele, Milan, Italy

    F Gangemi & M Degano

  10. Cleveland Clinic, Cleveland, OH, USA

    D S Bosler

  11. Hematology Department and HCT Unit, G Papanicolaou Hospital, Thessaloniki, Greece

    A Anagnostopoulos & K Stamatopoulos

  12. Department of Hematology, University of Palermo, Palermo, Italy

    E Iannitto

  13. Pathology Unit and Unit of Lymphoid Malignancies, Istituto Scientifico San Raffaele, Milan, Italy

    M Ponzoni

  14. Laboratory of Hematology, Hospices Civils de Lyon, Université Lyon 1, Lyon, France

    P Felman

  15. Hematology Department, Nikea General Hospital, Pireaus, Greece

    C Belessi

  16. Hematopathology Department, Evangelismos Hospital, Athens, Greece

    T Papadaki

  17. Department of Pathology, Mayo Clinic, Rochester, MN, USA

    A Dogan

  18. Hospital Universitario Marques de Valdecilla, Santander, Spain

    M A Piris

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  1. V Bikos
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  2. N Darzentas
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  9. D Gonzalez
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  19. P Felman
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  20. F Berger
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  21. C Belessi
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  22. P Ghia
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  23. T Papadaki
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  24. A Dogan
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  25. M Degano
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  26. E Matutes
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  27. M A Piris
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  28. D Oscier
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  29. K Stamatopoulos
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Correspondence to K Stamatopoulos.

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Bikos, V., Darzentas, N., Hadzidimitriou, A. et al. Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications. Leukemia 26, 1638–1646 (2012). https://doi.org/10.1038/leu.2012.3

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