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 Blood, 8 January 2009, Vol. 113, No. 2, pp. 403-411.
Prepublished online as a Blood First Edition Paper on October 23, 2008; DOI 10.1182/blood-2008-07-166868.

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LYMPHOID NEOPLASIA

Evidence for the significant role of immunoglobulin light chains in antigen recognition and selection in chronic lymphocytic leukemia

Anastasia Hadzidimitriou1,2,*, Nikos Darzentas1,*, Fiona Murray3,*, Tanja Smilevska2, Eleni Arvaniti4, Cristina Tresoldi5, Athanasios Tsaftaris1, Nikolaos Laoutaris4, Achilles Anagnostopoulos2, Frederic Davi6, Paolo Ghia7, Richard Rosenquist3, Kostas Stamatopoulos2, and Chrysoula Belessi4

1 Institute of Agrobiotechnology, Centre for Research and Technology, Thessaloniki, Greece; 2 Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece; 3 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; 4 Hematology Department, Nikea General Hospital, Athens, Greece; 5 HLA Tissue Typing, Immunohematology and Transfusion Medicine Service, Istituto Scientifico San Raffaele, Milan, Italy; 6 Laborary of Hematology and Université Pierre et Marie Curie, Hôpital Pitié-Salpètrière, Paris, France; and 7 Laboratory and Unit of Lymphoid Malignancies, Department of Oncology, Università Vita-Salute, San Raffaele and Istituto Scientifico San Raffaele, Milan, Italy

We analyzed somatic hypermutation (SHM) patterns and secondary rearrangements involving the immunoglobulin (IG) light chain (LC) gene loci in 725 patients with chronic lymphocytic leukemia (CLL). Important differences regarding mutational load and targeting were identified in groups of sequences defined by IGKV/IGLV gene usage and/or K/LCDR3 features. Recurrent amino acid (AA) changes in the IGKV/IGLV sequences were observed in subsets of CLL cases with stereotyped B-cell receptors (BCRs), especially those expressing IGHV3-21/IGLV3-21 and IGHV4-34/IGKV2-30 BCRs. Comparison with CLL LC sequences carrying heterogeneous K/LCDR3s or non-CLL LC sequences revealed that distinct amino acid changes appear to be "CLL-biased." Finally, a significant proportion of CLL cases with monotypic LC expression were found to carry multiple potentially functional LC rearrangements, alluding to active, (auto)antigen-driven receptor editing. In conclusion, SHM targeting in CLL LCs is just as precise and, likely, functionally driven as in heavy chains. Secondary LC gene rearrangements and subset-biased mutations in CLL LC genes are strong indications that LCs are crucial in shaping the specificity of leukemic BCRs, in association with defined heavy chains. Therefore, CLL is characterized not only by stereotyped HCDR3 and heavy chains but, rather, by stereotyped BCRs involving both chains, which generate distinctive antigen-binding grooves.


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L.-A. Sutton, E. Kostareli, A. Hadzidimitriou, N. Darzentas, A. Tsaftaris, A. Anagnostopoulos, R. Rosenquist, and K. Stamatopoulos
Extensive intraclonal diversification in a subgroup of chronic lymphocytic leukemia patients with stereotyped IGHV4-34 receptors: implications for ongoing interactions with antigen
Blood, November 12, 2009; 114(20): 4460 - 4468.
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