V(H) gene analysis of IgM-secreting myeloma indicates an origin from a memory cell undergoing isotype switch events.
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 V(H) gene sequences in 6 cases. Potentially functional tumor-derived V(H) genes were all derived from V(H)3, with the V(3-7) 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 Cgamma 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.
Molecular Immunology Group, Tenovus Laboratory, Department of Haematology, Southampton University Hospitals, Southampton, UK. ss1@sonton.ac.uk
S S
SS
Sahota
R
R
Garand
R
R
Mahroof
A
A
Smith
N
N
Juge-Morineau
F K
FK
Stevenson
R
R
Bataille
D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001483:Base Sequence; D005803:Genes, Immunoglobulin; D006801:Humans; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000276:immunology; D007156:Immunologic Memory; D008875:Middle Aged; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology*
D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region