Origins of the malignant clone in typical Waldenstrom's macroglobulinemia

Histopathology and phenotypic considerations in IgM-secreting B-cell tumors allow distinction between different diseases, but insight into pathogenesis is restricted. Here, variable region (V) gene analysis can complement classification but, more importantly, can also reveal disease origins and clonal history. We used V(H) gene analysis to probe origins in Waldenstrom's macroglobulinemia (WM), and contrasted these with the less malignant counterpart, IgM-secreting monoclonal gammopathy of undetermined significance (MGUS). Limited data on WM sequences had previously shown evidence for somatic mutation, but with conflicting analysis of intraclonal variation in tumor sequences. To further the investigation, we analyzed seven cases of WM and compared these with three cases of IgM MGUS. In both diseases, V(H) genes were somatically mutated with no evidence of intraclonal variation, even at the MGUS stage. A sensitive V(H) gene-probe assay revealed no evidence for isotype switch transcripts in any of the WM and IgM MGUS cases. These findings reveal an origin of WM and IgM MGUS from a IgM cell, which transforms after cessation of somatic mutation but without initiating switch events. In contrast, IgM-secreting multiple myeloma arises at a later stage in differentiation, when isotype switch mechanisms have been engaged.