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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1524-1533.
Prepublished online as a Blood First Edition Paper on October 24, 2007; DOI 10.1182/blood-2007-07-099564.
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Submitted July 6, 2007
Accepted October 4, 2007
Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis
Fiona Murray, Nikos Darzentas, Anastasia Hadzidimitriou, Gerard Tobin, Myriam Boudjogra, Cristina Scielzo, Nikolaos Laoutaris, Karin Karlsson, Fanny Baran-Marzsak, Athanasios Tsaftaris, Carol Moreno, Achilles Anagnostopoulos, Federico Caligaris-Cappio, Dominique Vaur, Christos Ouzounis, Chrysoula Belessi, Paolo Ghia*, Fred Davi, Richard Rosenquist, and Kostas Stamatopoulos
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
Computational Genomics Unit/Institute of Agrobiotechnology, Centre for Research and Technology, Thessaloniki, Greece
Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
Laboratory 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 and Instituto Scientifico San Raffaele, Milano, Italy
Hematology Department, Nikea General Hospital, Athens, Greece
Department of Hematology, Lund University Hospital, Lund, Sweden
Laborary of Hematology, Hopital Avicenne and EA 3046 Universite Paris 13, Bobigny, France
Institute of Hematology and Oncology, and Institute d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain
Laboratory of Biology and Oncology, Centre Francois Baclesse, Caen, France
* Corresponding author; email: ghia.paolo{at}hsr.it.
We have examined somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) and compared them with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with <100% identity to germline. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (i) IGHV gene usage; (ii) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences; and (iii) mutational load. We demonstrate that recurrent, "stereotyped" amino acid changes occur across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are under-represented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, we show that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The very precise targeting and distinctive features of SHM in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).
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