MYELOMA V-L AND V-H GENE-SEQUENCES REVEAL A COMPLEMENTARY IMPRINT OF ANTIGEN SELECTION IN TUMOR-CELLS

In multiple myeloma, sequence studies of V-H genes used to encode clon al lg in neoplastic plasma cells have shown a common pattern of extens ive somatic hypermutation. A further consistent feature of these V-H s equences is a complete lack of intraclonal variation. These findings i ndicate that the malignant cell arises at a mature, postfollicular sta ge of B-cell development. However, only a minority of cases have a dis tribution of somatic mutations in V-H consistent with a prior role for antigen in selecting the B cell of origin. To complement these studie s, and to take further the investigation of a role for antigen in the clonal history of myeloma, we have investigated tumor-derived V-L sequ ences from bone marrows of 15 patients. All sequences (9V kappa and 6V lambda) were potentially functional and 5 of 15 had evidence for N-re gion additions. All had undergone extensive somatic hypermutation, and showed no intraclonal variation. In 4 of 15 cases, the distribution o f mutations revealed a significant (P <.05) clustering of replacement mutations in the CDR sequences, indicating a role for V-L in selection by antigen. Comparison with the V-H sequences used by the same tumor cells showed that, if significant clustering was present, it was in ei ther V, or V-L but not both. Altogether, 10 of 15 V-regions showed evi dence for antigen selection, suggesting that the B cell of origin has behaved as a normal germinal center B cell. Deductions concerning a ro le for antigen selection may require both V-H and V-L sequences for va lidation. d(C) 1997 by The American Society of Hematology.