![]() ![]() 1 The characterization of VDJ H rearrangements as well as related processes such as somatic hypermutation (SHM) and class switch recombination (CSR) may help to shed light on this area because the differentiation process follows a strict hierarchical order in generating the Ig repertoire. ![]() Although clearly defined and reproducible criteria distinguish between IgM-MGUS and WM, the precise cells from which these two entities originate remains unclear. 2 Both conditions typically have a monoclonal component (M-component) produced by monoclonal B-cells harboring a unique clonotypic rearrangement of immunoglobulin heavy chain gene ( IgH), the VDJ H rearrangement, associated with a specific constant region IgM. 1 It is conceivable that WM evolves from an IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), although this has only been demonstrated in approximately 8% of all WM cases. Waldenström’s macroglobulinemia (WM) is an uncommon lymphoproliferative disorder primarily characterized by the presence of an immunoglobulin M (IgM), monoclonal protein and unequivocal evidence of bone marrow infiltration by lymphoplasmacytic lymphoma. 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. ![]() Interpretation and Conclusions WM and IgM-MGUS exhibit dissimilarities in VDJ H and DJ H rearrangements that could suggest different differentiation processes. IgA and/or IgG monoclonal isotypes were seen in three WM cases (14%) but in none of the IgM-MGUS patients. IgM clonotypic transcripts were observed in all cases and IgD in 83%. All DJ H rearrangements were unmutated, which makes them an attractive target for minimal residual disease investigation. DJ H rearrangements were more frequent in WM than in MGUS (42% and 13%, respectively). Somatic hypermutation with >2% deviation was seen in 90% of cases of WM and in 71% of IgM-MGUS. The distribution of both D H and J H families in WM did not differ from that in normal B-lymphocytes. The V H3-23 segment was never selected in IgM-MGUS. 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. 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. Twenty-nine of them were also tested for the existence of class switch recombination (CSR). 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. The aim of this study was to characterize IgH rearrangements in a larger series of IgM-related disorders than any previously described. 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). ![]()
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