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

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Blood First Edition Paper, prepublished online October 23, 2008; DOI

10.1182/blood-2008-07-166868.

Evidence for the significant role of immunoglobulin light chains in antigen

recognition and selection in chronic lymphocytic leukemia

Anastasia Hadzidimitriou, Nikos Darzentas, Fiona Murray, Tanja Smilevska, Eleni

Arvaniti, Cristina Tresoldi, Athanasios Tsaftaris, Nikolaos Laoutaris, Achilles

Anagnostopoulos, Frederic Davi, Paolo Ghia*, Rosenquist, Kostas

Stamatopoulos, and Chrysoula Belessi

Institute of Agrobiotechnology, Centre for Research and Technology,

Thessaloniki, Greece

Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University,

Uppsala, Sweden

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

Greece

Hematology Department, Nikea General Hospital, Athens, Greece

HLA Tissue Typing, Immunohematology and Transfusion Medicine Service, Istituto

Scientifico San Raffaele, Milan, Italy

Laborary of Hematology and Universite Pierre et Marie Curie, Hopital

Pitie-Salpetriere, Paris, France

Laboratory and Unit of Lymphoid Malignancies, Department of Oncology, Universita

Vita-Salute San Raffaele, Milano, Italy

* Corresponding author; email: ghia.paolo@... .

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 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.