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Chronic Lymphocytic Leukemia

Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases

Leukemia volume 25, pages 979–984 (2011)Cite this article

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Abstract

Immunoglobulin gene sequence analysis is widely utilized for prognostication in chronic lymphocytic leukemia (CLL) and the definition of standardized procedures has allowed reliable and reproducible results. Occasionally, a straightforward interpretation of the sequences is not possible because of the so-called ‘problematic sequences’ that do not fit the ‘classic’ interpretation and pose scientific questions at the cross-road between hematology and immunology. Thanks to a dedicated effort within the European Research Initiative on CLL (ERIC), we have now the possibility to present such cases, offer a scientific explanation and propose recommendations in terms of prognostication.

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References

  1. Stamatopoulos K, Ghia P, Rosenquist R (eds). New Biological Prognostic Markers in Chronic Lymphocytic Leukemia. WKHealth Books: Milan, 2010.

    Google Scholar 

  2. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen S et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–1847.

    CAS  PubMed  Google Scholar 

  3. 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: 1848–1854.

    CAS  PubMed  Google Scholar 

  4. Ghia P, Stamatopoulos K, Belessi C, Moreno C, Stilgenbauer S, Stevenson F et al. European Research Initiative on CLL. ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia. Leukemia 2007; 21: 1–3.

    Article  CAS  PubMed  Google Scholar 

  5. Lefranc M-P, Giudicelli V, Ginestoux C, Jabado-Michaloud J, Folch G, Bellahcene F et al. IMGT®, the international ImMunoGeneTics information system®. Nucl Acids Res 2009; 37: D1006–D1012.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Belessi C . Interpretation of ‘trouble’ sequences. In: Immunoglobulin Gene Analysis in Chronic Lymphocytic Leukemia, Chapter 3. Ghia P, Davi F, Rosenquist R (eds). WKHealth: Milan, 2008.

    Google Scholar 

  8. Belessi C, Davi F, Stamatopoulos K, Degano M, Andreou T, 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: 1963–1974.

    Article  CAS  PubMed  Google Scholar 

  9. Steenbergen EJ, Verhagen OJ, van den Berg H, van Leeuwen EF, Behrendt H, Slater RR et al. Rearrangement status of the malignant cell determines type of secondary IgH rearrangement (V-replacement or V to DJ joining) in childhood B precursor acute lymphoblastic leukemia. Leukemia 1997; 11: 1258–1265.

    Article  CAS  PubMed  Google Scholar 

  10. Schlissel M . Allelic exclusion of immunoglobulin gene rearrangement and expression: why and how? Semin Immunol 2002; 14: 207–212.

    Article  CAS  PubMed  Google Scholar 

  11. Li Y, Li H, Weigert M . Autoreactive B cells in the marginal zone that express dual receptors. J Exp Med 2002; 195: 181–188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rassenti LZ, Kipps TJ . Lack of allelic exclusion in B cell chronic lymphocytic leukemia. J Exp Med 1997; 185: 1435–1445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hadzidimitriou A, Darzentas N, Murray F, Smilevska T, Arvaniti E, Tresoldi C et al. Evidence for the significant role of immunoglobulin light chains in antigen recognition and selection in chronic lymphocytic leukemia. Blood 2009; 113: 403–411.

    Article  CAS  PubMed  Google Scholar 

  14. Sanchez ML, Almeida J, Gonzalez D, Gonzalez M, Garcia-Marcos MA, Balanzategui A et al. Incidence and clinicobiologic characteristics of leukemic B-cell chronic lymphoproliferative disorders with more than one B-cell clone. Blood 2003; 102: 2994–3002.

    Article  CAS  PubMed  Google Scholar 

  15. 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: 1636–1643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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: 1524–1533.

    Article  CAS  PubMed  Google Scholar 

  17. Seiler T, Woelfle M, Yancopoulos S, Catera R, Li W, Hatzi K et al. Characterization of structurally defined epitopes recognized by monoclonal antibodies produced by chronic lymphocytic leukemia B cells. Blood 2009; 114: 3615–3624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tobin G, Thunberg U, Johnson A, Thörn I, Söderberg O, Hultdin M et al. Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood 2002; 99: 2262–2264.

    Article  CAS  PubMed  Google Scholar 

  19. 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: 1678–1685.

    Article  CAS  PubMed  Google Scholar 

  20. Thorselius M, Krober A, Murray F, Thunberg U, Tobin G, Bühler A et al. Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-utilizing chronic lymphocytic leukemia independent of geographical origin and mutational status. Blood 2006; 107: 2889–2894.

    Article  CAS  PubMed  Google Scholar 

  21. 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: 259–270.

    Article  CAS  PubMed  Google Scholar 

  22. 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: 492–506.

    Article  PubMed  Google Scholar 

  23. Oscier D, Wade R, Davis Z, Morilla A, Best G, Richards S et al. Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica 2010; 95: 1705–1712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lefranc M-P, Lefranc G . The Immunoglobulin FactsBook, 1st edn, Academic Press: London, 2001, pp 1–458.

    Google Scholar 

  25. Lefranc M-P, Pommié C, Ruiz M, Giudicelli V, Foulquier E, Truong L et al. IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains. Dev Comp Immunol 2003; 27: 55–77.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Professor Marie-Paule Lefranc and Dr Veronique Giudicelli, Laboratoire d’Immunogenetique Moleculaire, LIGM, Universite Montpellier II, Montpellier, France, for both their long-standing collaboration with our group and their invaluable guidance to immunoglobulin gene sequence analysis. We also thank the following members of our groups for their assistance with both technical and methodological issues as well as the interpretation of immunoglobulin gene sequence results: Elena Arvaniti, Myriam Boudjoghra, Lone Bredo Pedersen, Victoria Bryant, Nicola Cahill, Antonis Dagklis, Vassiliki Douka, Ellen van Gastel-Mol, Mattias Jansson, Tatjana Smilevska, Gerard Tobin, Eugenia Tsakou, Ulf Thunberg and Isla Wheatley. Finally, we acknowledge the collaboration of Gabriele Strache who set up the webpage of the ERIC Review Board and is taking care of its maintenance. This work was supported by the Swedish Cancer Society and the Swedish Medical Research Council; the Program grant in Molecular Clinical Oncology-5 per mille # 9965 and Investigator grant, Associazione Italiana per la Ricerca sul Cancro Milano, Italy; PRIN-MIUR, Rome, Italy, Progetti Integrati Oncologia (PIO)–Ministero della Salute, Rome, Italy; the CARIPLO-Foundation, Milano, Italy; the Tenovus UK, Tenovus Solentside and the Experimental Cancer Medicine Centre (ECMC) network; the French Ministry of Health; ENosAI project (code 09SYN-13-880), co-funded by the EU and the Hellenic General Secretariat for Research and Technology; and the Greek Ministry of Health.

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Authors and Affiliations

  1. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    A W Langerak

  2. Laboratory of Hematology and Université Pierre et Marie Curie, Hôpital Pitié-Salpètrière, Paris, France

    F Davi

  3. Division of Molecular Oncology and Department of Oncology, Laboratory of B Cell Neoplasia and Unit of Lymphoid Malignancies, Università Vita-Salute San Raffaele and Istituto Scientifico San Raffaele, Milan, Italy

    P Ghia

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

    A Hadzidimitriou & K Stamatopoulos

  5. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    F Murray & R Rosenquist

  6. Cancer Sciences Division, Somers Cancer Research Building, University of Southampton, Southampton, UK

    K N Potter

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

    K Stamatopoulos

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

    C Belessi

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  1. A W Langerak
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on behalf of the European Research Initiative on CLL (ERIC)

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Correspondence to P Ghia.

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Langerak, A., Davi, F., Ghia, P. et al. Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases. Leukemia 25, 979–984 (2011). https://doi.org/10.1038/leu.2011.49

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