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

Abstract

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 VDJH and DJH rearrangements. Twenty-nine of them were also tested for the existence of class switch recombination (CSR). Results: VDJH and DJH 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 VH family and single segment were VH3 and VH3-23 (76% and 29%, respectively), with their frequencies differing markedly from those that would occur if the rearrangements were random. The VH3-23 segment was never selected in IgM-MGUS. The distribution of both DH and JH 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. DJH rearrangements were more frequent in WM than in MGUS (42% and 13%, respectively). All DJH 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 VDJH and DJH 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. ©2007 Ferrata Storti Foundation.