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Chronic Lymphocytic Leukemia

A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence

Leukemia volume 24, pages 125–132 (2010)Cite this article

Abstract

Chronic lymphocytic leukemia (CLL) is uniquely characterized by the existence of subsets of cases with quasi-identical, ‘stereotyped’ B-cell receptors (BCRs). Herein we investigate this stereotypy in 2662 patients with CLL, the largest series yet, using purpose-built bioinformatics methods based on sequence pattern discovery. Besides improving the identification of ‘stereotyped’ cases, we demonstrate that CLL actually consists of two different categories, based on the BCR repertoire, with important biological and ontogenetic differences. The first (∼30% of cases) shows a very restricted repertoire and is characterized by BCR stereotypy (clustered cases), whereas the second includes cases with heterogeneous BCRs (nonclustered cases). Eleven major CLL clusters were identified with antigen-binding sites defined by just a few critically positioned residues, regardless of the actual immunoglobulin (IG) variable gene used. This situation is closely reminiscent of the receptors expressed by cells participating in innate immune responses. On these grounds, we argue that whereas CLL cases with heterogeneous BCRs likely derive from the conventional B-cell pool, cases with stereotyped BCRs could derive from progenitor cells evolutionarily adapted to particular antigenic challenges, perhaps intermediate between a true innate immune system and the conventional adaptive B-cell immune system, functionally similar to what has been suggested previously for mouse B1 cells.

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Acknowledgements

We thank Prof Marie-Paule Lefranc and Dr Veronique Giudicelli, Laboratoire d'Immunogenetique Moleculaire, LIGM, Universite Montpellier II, Montpellier, France, for their enormous support and help with the large-scale immunoglobulin sequence analysis throughout this project. We also thank Prof Göran Roos, Department of Medical Biosciences, Umeå University, Sweden; Prof Christer Sundström, Department of Genetics and Pathology, Uppsala University, Sweden; Dr Mats Merup, Department of Medicine, Karolinska University Hospital, Huddinge, Sweden; Dr Lyda Osorio, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Dr Karin Karlsson, Department of Hematology, Lund University Hospital, Lund, Sweden and Prof Juhani Vilpo, Laboratory Centre, Tampere University Hospital, Tampere, Finland for providing samples and clinical data concerning Swedish and Finnish CLL patients. We also acknowledge the contribution of Dr Tatjana Smilevska, Dr Gerard Tobin, Dr Ulf Thunberg, Maria Norberg, Arifin Kaderi, Ingrid Thörn and Kerstin Willander to the sequence analysis. This work was supported by the General Secretariat for Research and Technology of Greece (INA-GENOME and ENTER programs); the BioSapiens Network of Excellence (contract number LSHG-CT-2003–503265); the Swedish Cancer Society; the Swedish Research Council, Medical Faculty of Uppsala University, Uppsala University Hospital; the Lion's Cancer Research Foundation, Uppsala, Sweden; the Associazione Italiana per la Ricerca sul Cancro—AIRC, Milano, Italy; Progetto Integrato Oncologia, Italian Ministry of Health, Rome, Italy; Fondazione Anna Villa e Felice Rusconi, Varese, Italy; Project C03/10 from ‘Redes Temáticas de Investigación Cooperativa’, Ministerio de Sanidad y Consumo (2003), Spain and the José Carreras International Foundation Against Leukemia (CR/07 and EM/07).

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Authors and Affiliations

  1. Centre for Research and Technology Hellas, Institute of Agrobiotechnology, Thessaloniki, Greece

    N Darzentas, A Hadzidimitriou & A Tsaftaris

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

    A Hadzidimitriou, A Anagnostopoulos & K Stamatopoulos

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

    F Murray & R Rosenquist

  4. The Feinstein Institute for Medical Research, North Shore–LIJ Health System, Manhasset, NY, USA

    K Hatzi & N Chiorazzi

  5. Department of Hematology, Rigshospitalet, Copenhagen, Denmark

    P Josefsson & J Jurlander

  6. Department of Hematology, Nikea General Hospital, Athens, Greece

    N Laoutaris & C Belessi

  7. Institute of Hematology and Oncology, Hospital Clinic, University of Barcelona, Barcelona, Spain

    C Moreno

  8. Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic, University of Barcelona, Barcelona, Spain

    C Moreno

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

    P Ghia

  10. Istituto Scientifico San Raffaele, Milan, Italy

    P Ghia

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

    F Davi

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Correspondence to P Ghia.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Darzentas, N., Hadzidimitriou, A., Murray, F. et al. A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence. Leukemia 24, 125–132 (2010). https://doi.org/10.1038/leu.2009.186

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