Immunoglobulin Heavy- And Light-chain Repertoire in Splenic Marginal Zone Lymphoma
The considerable heterogeneity in morphology, immunophenotype, genotype, and clinical behavior of splenic marginal zone lymphoma (SMZL) hinders firm conclusions on the origin and differentiation stage of the neoplastic cells. Immunoglobulin (IG) gene usage and somatic mutation patterns were studied in a series of 43 SMZL cases. Clonal IGHV-D-J rearrangements were amplified in 42/43 cases (4 cases carried double rearrangements). Among IGHV-D-J rearrangements, IGHV3 and IGHV4 subgroup genes were used with the highest frequency. Nineteen IGHV genes were unmutated (>98% homology to the closest germline IGHV gene), whereas 27/46 were mutated. Clonal IGKV-J and IGLV-J gene rearrangements were amplified in 36/43 cases, including 31 IGKV-J (8/31 in lambda light-chain expressing cases) and 12 IGLV-J rearrangements; 9/31 IGKV and 6/12 IGLV sequences were mutated. IGKV-J and IGLV-J rearrangements used 14 IGKV and 9 IGLV different germline genes. Significant evidence for positive selection by classical T-dependent antigen was found in only 5/27 IGHV and 6/15 IGKV+IGLV mutated genes. These results provide evidence for the diverse B-cell subpopulations residing in the SMZ, which could represent physiologic equivalents of distinct SMZL subtypes. Furthermore, they indicate that in SMZL, as in other B cell malignancies, a complementarity imprint of antigen selection might be witnessed either by IGHV, IGKV, or IGLV rearranged sequences.
We are indebted to Prof. Marie-Paule Lefranc and Dr. Veronique Giudicelli (Laboratoire d’Immunogenetique Moleculaire, LIGM, Universite Montpellier II, UPR CNRS) for sharing with us a wealth of insight on immunoglobulin genes and offering valuable help in data analysis. We also wish to thank Prof. Manlio Ferrarini (Istituto Nazionale per la Ricerca sul Cancro and Dipartmento di Oncologia Clinica e Sperimentale, Universita di Genova) and Prof. Nicholas Chiorrazzi (North Shore-Long Island Jewish Research Institute, Manhasset, New York) for helpful discussions and their support and interest in our work.
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