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

To further characterize the B-cell origin of multiple myeloma, our lab oratory performed immunoglobulin gene sequence analyses of four cases of myeloma (three immunoglobulin A and one immunoglobulin G). Three tu mors expressed V(H)3 genes and one expressed a V(H)1 gene, while the l ight chains included two V-lambda and one VkappaIII; one light chain w as not isolated, The closest homology to published germ line genes ran ged from 91 to 97%, In two cases, the expressed V-H genes were compare d with the putative germ line precursor V-H genes isolated from autolo gous granulocyte DNA and appeared to have mutated randomly from the ge rm line gene, By sequencing multiple clonal isolates from each tumor s ample, we found no evidence for ongoing mutation in three cases; in on e case, however, clonotypic heterogeneity was evident, The analysis of D-H- and J(H)-region genes revealed (i) limited or absent N nucleotid e insertions (two of four cases), (ii) the presence of a D-H-J(H) junc tion resulting from sequence overlap between the D-H and J(H) genes (o ne 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 tha t multiple myeloma, similar to what has been proposed for chronic lymp hocytic leukemia, may derive from B cells which have rearranged during fetal development rather than during adult life.