Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations

• Published in: Blood 2007-01, Vol.109 (1), p.259-270
• Main Authors: Stamatopoulos, Kostas, Belessi, Chrysoula, Moreno, Carol, Boudjograh, Myriam, Guida, Giuseppe, Smilevska, Tatjana, Belhoul, Lynda, Stella, Stefania, Stavroyianni, Niki, Crespo, Marta, Hadzidimitriou, Anastasia, Sutton, Laurent, Bosch, Francesc, Laoutaris, Nikolaos, Anagnostopoulos, Achilles, Montserrat, Emili, Fassas, Athanasios, Dighiero, Guillaume, Caligaris-Cappio, Federico, Merle-Béral, Hélène, Ghia, Paolo, Davi, Frédéric
• Format: Article
• Language: English
• Subjects: ADP-ribosyl Cyclase 1 - analysis; Amino Acid Sequence; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - pathology; Base Sequence; Biological and medical sciences; Cohort Studies; Epitopes; Follow-Up Studies; France; Gene Frequency; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Genes, Immunoglobulin; Greece; Hematologic and hematopoietic diseases; Humans; Immunoglobulin Class Switching; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Switch Region; Immunoglobulin Variable Region - genetics; Italy; Leukemia, Lymphocytic, Chronic, B-Cell - etiology; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Molecular Sequence Data; Polymerase Chain Reaction; Rheumatoid Factor - immunology; Sequence Homology; Somatic Hypermutation, Immunoglobulin; Spain
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-03-012948

The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is biased and characterized by the existence of subsets of cases with closely homologous (“stereotyped”) complementarity-determining region 3 (CDR3) sequences. In the present series, 201 (21.9%) of 916 patients with CLL expressed IGHV genes that belonged to 1 of 48 different subsets of sequences with stereotyped heavy chain (H) CDR3. Twenty-six subsets comprised 3 or more sequences and were considered “confirmed.” The remaining subsets comprised pairs of sequences and were considered “potential”; public database CLL sequences were found to be members of 9 of 22 “potential” subsets, thereby allowing us to consider them also “confirmed.” The chance of belonging to a subset exceeded 35% for unmutated or selected IGHV genes (eg, IGHV1-69/3-21/4-39). Comparison to non-CLL public database sequences showed that HCDR3 restriction is “CLL-related.” CLL cases with selected stereotyped immunoglobulins (IGs) were also found to share unique biologic and clinical features. In particular, cases expressing stereotyped IGHV4-39/IGKV1-39-1D-39 and IGHV4-34/IGKV2-30 were always IgG-switched. In addition, IGHV4-34/IGKV2-30 patients were younger and followed a strikingly indolent disease, contrasting other patients (eg, those expressing IGHV3-21/IGLV3-21) who experienced an aggressive disease, regardless of IGHV mutations. These findings suggest that a particular antigen-binding site can be critical in determining the clinical features and outcome for at least some CLL patients.