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Chronic Lymphocytic Leukemia

Intraclonal diversification of immunoglobulin light chains in a subset of chronic lymphocytic leukemia alludes to antigen-driven clonal evolution

Leukemia volume 24, pages 1317–1324 (2010)Cite this article

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Abstract

The study of intraclonal diversification (ID) in immunoglobulin (IG) genes offers valuable insight into the role of ongoing interactions with antigen in lymphomagenesis. We recently showed that ID in the IG heavy chain genes of patients with chronic lymphocytic leukemia (CLL) was generally limited; however, intense ID was evident in selected cases, especially those expressing stereotyped IGHV4-34 rearrangements and assigned to subset 4. Here, we report results from a large-scale subcloning study of IG light variable genes, in a total of 1008 subcloned sequences from 56 CLL cases. Multiple analogies were noted between heavy and light chains regarding the occurrence and molecular features of ID. More specifically, the impact of ID on the clonotypic light chains was generally low, with the significant exception of subset 4. Similar to the IGHV4-34 heavy chains of this subset, their partner IGKV2-30 light chains were affected by an active and precisely targeted ID process. Altogether, these findings strengthen the argument that stereotypy in subset 4 extends to stereotyped ID patterns for both heavy and light chains through persistent antigenic stimulation. Furthermore, they strongly suggest that light chains have an active role in the antigen selection process, at least for certain subsets of CLL cases.

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Acknowledgements

We thank Professor Marie-Paule Lefranc and Dr Veronique Giudicelli, Laboratoire d’Immunogenetique Moleculaire, LIGM, Universite Montpellier II, Montpellier, France, for their long-standing support and guidance with the large-scale immunoglobulin sequence analysis throughout this project. We also acknowledge the contribution of Christer Sundström, Karin Karlsson and Juhani Vilpo for providing samples and associated data, and Andreas Agathagelidis, Vasilis Bikos, Nikos Papakonstantinou, Gerard Tobin, Ulf Thunberg and Mia Thorsélius to the sequence analysis. This work was supported by the Swedish Cancer Society, the Swedish Medical Research Council, the Medical Faculty of Uppsala University, Uppsala University Hospital, and the Lion's Cancer Research Foundation, Uppsala, Sweden; the BioSapiens Network of Excellence (contract number LSHG-CT-2003-503265); and, the General Secretariat for Research and Technology of Greece (Program INA-GENOME). EK is a recipient of a fellowship from the Propondis Foundation, Athens, Greece.

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Author notes

  1. E Kostareli and L-A Sutton: These authors contributed equally to this work.

  2. R Rosenquist and K Stamatopoulos: These senior authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece

    E Kostareli & A Kouvatsi

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

    E Kostareli, A Anagnostopoulos & K Stamatopoulos

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

    L-A Sutton & R Rosenquist

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

    A Hadzidimitriou, N Darzentas & A Tsaftaris

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  1. E Kostareli
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Correspondence to K Stamatopoulos.

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Kostareli, E., Sutton, LA., Hadzidimitriou, A. et al. Intraclonal diversification of immunoglobulin light chains in a subset of chronic lymphocytic leukemia alludes to antigen-driven clonal evolution. Leukemia 24, 1317–1324 (2010). https://doi.org/10.1038/leu.2010.90

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