IMMUNOGLOBULIN GENE SEQUENCE-ANALYSIS TO FURTHER ASSESS B-CELL ORIGIN OF MULTIPLE-MYELOMA

To further characterize the B-cell origin of multiple myeloma, our laboratory performed immunoglobulin gene sequence analyses of four cases of myeloma (three immunoglobulin A and one immunoglobulin G). Three tumors expressed V(H)3 genes and one expressed a V(H)1 gene, while the light chains included two V-lambda and one VkappaIII; one light chain was not isolated, The closest homology to published germ line genes ranged from 91 to 97%, In two cases, the expressed V-H genes were compared with the putative germ line precursor V-H genes isolated from autologous granulocyte DNA and appeared to have mutated randomly from the germ line gene, By sequencing multiple clonal isolates from each tumor sample, we found no evidence for ongoing mutation in three cases; in one case, however, clonotypic heterogeneity was evident, The analysis of D-H- and J(H)-region genes revealed (i) limited or absent N nucleotide insertions (two of four cases), (ii) the presence of a D-H-J(H) junction resulting from sequence overlap between the D-H and J(H) genes (one of four cases), (iii) the absence of somatic mutations (two of four cases), and (iv) restricted J(H) gene usage of a J(H)6 polymorphism (three of four cases), These analyses of D-H and J(H) genes suggest that multiple myeloma, similar to what has been proposed for chronic lymphocytic leukemia, may derive from B cells which have rearranged during fetal development rather than during adult life.