title: Clues to pathogenesis of Waldenström macroglobulinemia and immunoglobulin M monoclonal gammopathy of undetermined significance provided by analysis of immunoglobulin heavy chain gene rearrangement and clustering of B-cell receptors.
abstract: We characterized immunoglobulin heavy chain (IGH) gene rearrangements and searched for clusters of stereotyped B-cell receptors in 123 patients with Waldenström macroglobulinemia (WM; n = 59) or immunoglobulin M monoclonal gammopathy of undetermined significance (IgM-MGUS) (n = 64). A productive monoclonal IGHV-D-J rearrangement was obtained in 99/123 patients (80%). Immunoglobulin heavy chain variable (IGHV) genes were mutated in 94/99 patients (95%) with a median somatic hypermutation rate of 6.7% (2.1-14.5). Compared with the normal B-cell repertoire, patients with WM/IgM-MGUS showed an over-representation of the IGHV3 subgroup (83% vs. 55%, p < 0.0001) and an under-representation of IGHV1 (7% vs. 14%, p = 0.04) and IGHV4 (7% vs. 23%, p = 0.0001) subgroups. At the gene level, in WM/IgM-MGUS there was an over-representation of IGHV3-23 (24% vs. 12%, p = 0.0003), IGHV3-64 (3% vs. < 1%, p = 0.003), IGHV3-7 (12% vs. 4%, p = 0.0001) and IGHV3-74 (9% vs. 2%, p < 0.0001), while IGHV4-39 was never used (0 vs. 5%, p = 0.03). Intra-WM/IgM-MGUS search for HCDR3 similarity showed no association fulfilling criteria for stereotyped receptors. WM/IgM-MGUS sequences were unrelated to known chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL) or mantle cell lymphoma (MCL) subsets. In conclusion, the IGHV gene usage in WM and IgM-MGUS is remarkably biased as compared to the normal B-cell repertoire. WM and IgM-MGUS-specific HCDR3 clusters do not occur with a frequency detectable with currently available databases, not supporting a B-cell receptor-driven pathogenesis in WM and IgM-MGUS.
authors: Department of Hematology-Oncology, Fondazione IRCCS Policlinico San Matteo , Pavia , Italy.
authors: Marzia
authors: M
authors: Varettoni
authors: Silvia
authors: S
authors: Zibellini
authors: Daniela
authors: D
authors: Capello
authors: Luca
authors: L
authors: Arcaini
authors: Davide
authors: D
authors: Rossi
authors: Cristiana
authors: C
authors: Pascutto
authors: Sara
authors: S
authors: Rattotti
authors: Silvia
authors: S
authors: Mangiacavalli
authors: Lara
authors: L
authors: Pochintesta
authors: Manuel
authors: M
authors: Gotti
authors: Gianluca
authors: G
authors: Gaidano
authors: Mario
authors: M
authors: Cazzola
mesh_terms: D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D022801:Complementarity Determining Regions / Q000235:genetics; D015322:Gene Rearrangement, B-Lymphocyte; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007144:Immunoglobulin J-Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000097:blood; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000175:diagnosis / Q000235:genetics*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D008258:Waldenstrom Macroglobulinemia / Q000175:diagnosis / Q000235:genetics*
chemical_list: D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007144:Immunoglobulin J-Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell