VH Gene Analysis of IgM-Secreting Myeloma Indicates an Origin From a Memory Cell Undergoing Isotype Switch Events

Abstract

IgM-secreting plasma cell tumors are rare variants of typical isotype-switched multiple myeloma with a similar disease outcome. To probe the origin and clonal history of these tumors, we have analyzed VH gene sequences in 6 cases. Potentially functional tumor-derived VH genes were all derived from VH3, with the V3-7 gene segment being used by 4 of 6. All were somatically mutated, with a mean deviation from germline sequence of 5.2% (range, 3.1% to 7.1%). The distribution of replacement mutations was consistent with antigen selection in 4 of 6 cases, and no intraclonal heterogeneity was observed. Clonally related switched isotype transcripts were sought in 4 cases, and Cγ transcripts with tumor-derived CDR3 sequence were identified in 2 of 4. These findings indicate that IgM-secreting myelomas are arrested at a postfollicular stage at which somatic mutation has been silenced. Isotype switch variants show the cell of origin to be at the IgM to IgG switch point. These features indicate that the final neoplastic event has occurred at a stage immediately before that of typical isotype-switched myeloma. One possibility is that IgM myeloma involves the previously identified precursor cell of typical myeloma.