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Molecular characterization of heavy chain immunoglobulin gene rearrangements in Waldenström’s macroglobulinemia and IgM monoclonal gammopathy of undetermined significance

All authors from Servicio de Hematología, Hospital Universitario de Salamanca; Centro de Investigación del Cáncer (CIC), Universidad de Salamanca, Spain

Correspondence: Ramón García-Sanz, Department of Hematology, University Hospital of Salamanca, Paseo de San Vicente, 58-182, Salamanca, 37007 Spain E-mail: rgarcias{at}usal.es

Background and Objectives: Waldenström macroglobulinemia (WM) and monoclonal gammopathy of undetermined significance (MGUS) are IgM-related disorders in which monoclonal B cells harbor a unique clonotypic rearrangement of the immunoglobulin heavy chain gene (IgH). The aim of this study was to characterize IgH rearrangements in a larger series of IgM-related disorders than any previously described.

Design and Methods: Seventy-two patients with monoclonal IgM disorders (64 with WM and eight with IgM-MGUS) were studied to amplify and sequence both VDJ_H and DJ_H rearrangements. Twenty-nine of them were also tested for the existence of class switch recombination (CSR).

Results: VDJ_H and DJ_H rearrangements were detected in 91% and 42% of WM patients and in 100% and 13% of IgM-MGUS patients, respectively. In WM, the most frequently observed V_H family and single segment were V_H3 and V_H3-23 (76% and 29%, respectively), with their frequencies differing markedly from those that would occur if the rearrangements were random. The V_H3-23 segment was never selected in IgM-MGUS. The distribution of both D_H and J_H families in WM did not differ from that in normal B-lymphocytes. Somatic hypermutation with >2% deviation was seen in 90% of cases of WM and in 71% of IgM-MGUS. DJ_H rearrangements were more frequent in WM than in MGUS (42% and 13%, respectively). All DJ_H rearrangements were unmutated, which makes them an attractive target for minimal residual disease investigation. IgM clonotypic transcripts were observed in all cases and IgD in 83%. IgA and/or IgG monoclonal isotypes were seen in three WM cases (14%) but in none of the IgM-MGUS patients.

Interpretation and Conclusions: WM and IgM-MGUS exhibit dissimilarities in VDJ_H and DJ_H rearrangements that could suggest different differentiation processes. There is evidence that WM cells are able to undergo CSR in vivo, a fact that was initially thought to be impossible in this disease.

Key words: Waldenström’s macroglobulinemia, monoclonal gammopathy of undetermined significance, immunoglobulin rearrangements, class switch recombination.