Relevance of stereotyped B-cell receptors in the context of the molecular, cytogenetic and clinical features of chronic lymphocytic leukemia

• Published in: PloS one Vol. 6; no. 8; p. e24313
• Main Authors: Maura, Francesco, Cutrona, Giovanna, Fabris, Sonia, Colombo, Monica, Tuana, Giacomo, Agnelli, Luca, Matis, Serena, Lionetti, Marta, Gentile, Massimo, Recchia, Anna Grazia, Di Raimondo, Francesco, Musolino, Caterina, Ilariucci, Fiorella, Di Renzo, Nicola, Pesce, Emanuela, Molica, Stefano, Federico, Massimo, Cortelezzi, Agostino, Morabito, Fortunato, Ferrarini, Manlio, Neri, Antonino
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.08.2011; Public Library of Science (PLoS)
• Subjects: Abnormalities; Agent Orange; Amino acids; Antigens; B cells; Biology; Cancer; Care and treatment; CD38 antigen; Chains; Chromosomes; Chronic lymphocytic leukemia; Clinical outcomes; Clonal deletion; Complementarity; Complementarity Determining Regions - genetics; Complementarity Determining Regions - metabolism; Correlation analysis; Cytogenetic Analysis; Development and progression; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Homology; Humans; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Heavy Chains - metabolism; Immunoglobulins; Lesions; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - diagnosis; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphatic leukemia; Lymphocyte receptors; Lymphocytes B; Medical diagnosis; Medical research; Medical treatment; Medicine; Mutation; Neoplasm Staging; Patients; Prognosis; Receptors; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - metabolism; Trisomy; Working groups; ZAP-70 protein; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0024313

Highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3), are expressed in a recurrent fraction of patients affected by chronic lymphocytic leukemia (CLL). We investigated the IGHV status of 1131 productive IG rearrangements from a panel of 1126 CLL patients from a multicenter Italian study group, and correlated the presence and class of HCDR3 stereotyped subsets with the major cytogenetic alterations evaluated by FISH, molecular prognostic factors, and the time to first treatment (TTFT) of patients with early stage disease (Binet A). Stereotyped HCDR3 sequences were found in 357 cases (31.7%), 231 of which (64.7%) were unmutated. In addition to the previously described subsets, 31 new putative stereotypes subsets were identified. Significant associations between different stereotyped HCDR3 sequences and molecular prognostic factors, such as CD38 and ZAP-70 expression, IGHV mutational status and genomic abnormalities were found. In particular, deletion of 17p13 was significantly represented in stereotype subset #1. Notably, subset #1 was significantly correlated with a substantially reduced TTFT compared to other CLL groups showing unmutated IGHV, ZAP-70 or CD38 positivity and unfavorable cytogenetic lesions including del(17)(p13). Moreover, subset #2 was strongly associated with deletion of 13q14, subsets #8 and #10 with trisomy 12, whereas subset #4 was characterized by the prevalent absence of the common cytogenetic abnormalities. Our data from a large and representative panel of CLL patients indicate that particular stereotyped HCDR3 sequences are associated with specific cytogenetic lesions and a distinct clinical outcome.