Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 144, Issue 4, Pages 492-506Publisher
WILEY
DOI: 10.1111/j.1365-2141.2008.07469.x
Keywords
chronic lymphocytic leukaemia; B cell receptor; immunoglobulin genes; prognosis
Categories
Funding
- Ministero della Salute
- Associazione Italiana contro le Leucemie, linfomi e mielomi
- Venezia Section, Pramaggiore Group
- Programmi di Ricerca di Interesse Nazionale (P.R.I.N.)
- Fondo per gli Investimenti per la Ricerca di Base (F.I.R.B.)
- Novara-A.I.L
- Onlus, Novara
- Ricerca Sanitaria Finalizzata Regione Piemonte, Torino
- Associazione Italiana per la Ricerca sul Cancro
- Piano di Ateneo per la Ricerca (P.A.R.) 2005, University of Siena, Italy
- Hairy Cell Leukemia Research Foundation (Illinois, USA)
- Associazione 'Franca Capurro per Novara' Onlus, Novara, Italy
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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.
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