Molecular analysis of immunoglobulin genes in multiple myeloma

The study of immunoglobulin genes in multiple myeloma over the last five ye ars has provided important information regarding biology, ontogenetic locat ion, disease evolution, pathogenic consequences and tumor-specific therapeu tic intervention with idiotypic vaccination, Detailed analysis of V-H genes has revealed clonal relationship between switch variants expressed by the bone marrow plasma cell and myeloma progenitors in the marrow and periphera l blood. V-H gene usage is biased against V4-34 (encoding antibodies with c old agglutinin specificity; anti-l/i) explaining the absence of autoimmune phenomena in myeloma compared to other B-cell lymphoproliferative disorders . V-H genes accumulate somatic hypermutations following a distribution comp atible with antigen selection, but with no intraclonal heterogeneity. V-L g enes indicate a bias in usage of V kappa I family members and somatic hyper mutation, in line with antigen selection, of the expressed V kappa genes i s higher than any other B-cell lymphoid disorder. A complementary imprint o f antigen selection as evidenced by somatic hypermutation of either the V-H or V-L clonogenic genes has been observed. The absence of ongoing somatic mutations in either V-H or V-L genes gives rise to the notion that the cell of origin in myeloma is a post-germinal center memory B-cell. Clinical app lication of sensitive PCR methods in order to detect clonal immunoglobulin gene rearrangements has made relevant the monitoring and follow-up of minim al residual disease in stem cell autografts and after myeloablative therapy . The fact that surface immunoglobulin V-H and V-L sequences consitute uniq ue tumor-specific antigenic determinants has stimulated investigators to de vise strategies aiming to generate active specific immunity against the idi otype of malignant B-cells in myeloma by constructing vaccines based on exp ressed single-chain Fv fragments, DNA plasmids carrying V-H+V-L clonogenic genes for naked DNA vaccination, or dendritic cell-based vaccination armed with the tumor-specific idiotype.