Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study

• Published in: British journal of haematology 2009-02, Vol.144 (4), p.492-506
• Main Authors: Bomben, Riccardo, Dal Bo, Michele, Capello, Daniela, Forconi, Francesco, Maffei, Rossana, Laurenti, Luca, Rossi, Davide, Del Principe, Maria Ilaria, Zucchetto, Antonella, Bertoni, Francesco, Rossi, Francesca Maria, Bulian, Pietro, Cattarossi, Ilaria, Ilariucci, Fiorella, Sozzi, Elisa, Spina, Valeria, Zucca, Emanuele, Degan, Massimo, Lauria, Francesco, Del Poeta, Giovanni, Efremov, Dimitar G., Marasca, Roberto, Gaidano, Gianluca, Gattei, Valter
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; B cell receptor; Biological and medical sciences; Chromosome Aberrations; chronic lymphocytic leukaemia; Complementarity Determining Regions - genetics; Follow-Up Studies; Gene Expression Regulation, Leukemic; Gene Rearrangement, B-Lymphocyte; Genes, Immunoglobulin Heavy Chain; Hematologic and hematopoietic diseases; Humans; immunoglobulin genes; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Variable Region - genetics; Immunophenotyping; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Middle Aged; Prognosis; Receptors, Antigen, B-Cell - genetics; Somatic Hypermutation, Immunoglobulin; Time Factors
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2008.07469.x

Summary A fraction of chronic lymphocytic leukaemia (CLL) cases carry highly homologous B‐cell receptors (BCR), i.e. characterized by non‐random combinations of immunoglobulin heavy‐chain variable (IGHV) genes and heavy‐chain complementarity determining region‐3 (HCDR3), often associated with a restricted selection of IGVK/L light chains. Such ‘stereotyped’ BCR occur more frequently in CLL with unmutated (UM) than mutated (M) IGHV genes. We analysed 1426 IG rearrangements (from 1398 CLL cases) by a clustering driven by HCDR3 similarities. Molecular findings were correlated to time‐to‐treatment (TTT) and presence of known prognosticators. Sixty‐nine clusters (319 IG‐rearrangements, 22·4%) with stereotyped BCR were identified. Among 30 confirmed clusters (≥3 IG‐rearrangements/cluster), we found 14 novel clusters, of which 11 had M IG rearrangements (M clusters) and predominantly (8/11) used IGHV3 subgroup genes. Recurrent cluster‐biased amino acid changes were found throughout IGHV sequences of these ‘M clusters’. Regarding clinical outcome: (i) UM CLL from the IGHV1‐2/1‐3/1‐18/1‐46/7‐4‐1/IGKV1‐39 cluster had poorer prognosis than UM/M cases, or UM cases using the same IGHV genes but not in clusters; (ii) M CLL from the IGHV3‐21/IGLV3‐21 cluster had TTT similar to UM CLL, and shorter than M CLL expressing IGHV3‐21 but not in cluster. Altogether, our analysis identified additional molecular and clinical features for CLL expressing stereotyped BCR.