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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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NEOPLASIA
Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis
Fiona Murray1,
Nikos Darzentas2,
Anastasia Hadzidimitriou2,3,
Gerard Tobin1,
Myriam Boudjogra4,
Cristina Scielzo5,
Nikolaos Laoutaris6,
Karin Karlsson7,
Fanny Baran-Marzsak8,
Athanasios Tsaftaris2,
Carol Moreno9,
Achilles Anagnostopoulos3,
Federico Caligaris-Cappio5,
Dominique Vaur10,
Christos Ouzounis2,
Chrysoula Belessi6,
Paolo Ghia5,
Fred Davi4,
Richard Rosenquist1, and
Kostas Stamatopoulos3
1 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden;
2 Computational Genomics Unit, Institute of Agrobiotechnology, Centre for Research and Technology, Thessaloniki, Greece;
3 Hematology Department and Hematopoietic Cell Transplantation Unit, G. Papanicolaou Hospital, Thessaloniki, Greece;
4 Laboratory of Hematology and Université Pierre et Marie Curie, Hôpital Pitié-Salpètrière, Paris, France;
5 Laboratory and Unit of Lymphoid Malignancies, Department of Oncology, Università Vita-Salute, San Raffaele and Instituto Scientifico San Raffaele, Milano, Italy;
6 Hematology Department, Nikea General Hospital, Athens, Greece;
7 Department of Hematology, Lund University Hospital, Lund, Sweden;
8 Laboratory of Hematology, Hôpital Avicenne and EA 3046 Université Paris 13, Bobigny, France;
9 Institute of Hematology and Oncology and Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic, University of Barcelona, Barcelona, Spain; and
10 Laboratory of Biology and Oncology, Centre François Baclesse, Caen, France
Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared 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 less than 100% identity to germ line. 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: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, "stereotyped" amino acid changes occurred 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 underrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown 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 precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).
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