Origin and diversification of the clonogenic cell in multiple myeloma: lessons from the immunoglobulin repertoire

The study of immunoglobulin genes in multiple myeloma over the last decade has provided important information regarding biology, ontogenetic assignmen t, disease evolution, pathogenic consequences and tumor-specific therapeuti c intervention. Detailed analysis of V-H genes has revealed the clonal rela tionship between switch variants expressed by the bone marrow plasma cell a nd myeloma progenitors in the marrow and peripheral blood. Regarding V-H us age, a bias was found against the V4-34 gene encoding antibodies with cold agglutinin specificity (anti-I/i), thus explaining in part the absence of a utoimmune phenomena in myeloma compared to other B cell lymphoproliferative disorders. However, in some studies a substantial number of cases analyzed were carrying the rearranged Hum kappa v325 V kappa gene, known to be over utilized by B cell chronic lymphocytic leukemia clones and possessing auto antibody binding activity. V-H genes accumulate somatic hypermutations foll owing a distribution compatible with antigen selection, but with no intracl onal heterogeneity. The analysis of V kappa genes indicates a bias in usage of V kappa I family members; somatic hypermutation, in line with antigen s election, of the expressed V kappa genes is higher than any other B cell ly mphoid disorder. Similar conclusions were reached far V lambda genes; in th is case, the analysis raises the controversial issue of N nucleotide insert ion at V lambda-J lambda junctions, apparently as a result of TdT activity. A complementary imprint of antigen selection as evidenced by somatic hyper mutation of either the V-H or V-L clonogenic genes has been observed. The a bsence of ongoing somatic mutations in either V-H or V-L genes gives rise t o the notion that the cell of origin in myeloma is a post-germinal center m emory B cell.