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

Citation
C. Kosmas et al., Origin and diversification of the clonogenic cell in multiple myeloma: lessons from the immunoglobulin repertoire, LEUKEMIA, 14(10), 2000, pp. 1718-1726
Citations number
92
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
LEUKEMIA
ISSN journal
08876924 → ACNP
Volume
14
Issue
10
Year of publication
2000
Pages
1718 - 1726
Database
ISI
SICI code
0887-6924(200010)14:10<1718:OADOTC>2.0.ZU;2-X
Abstract
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.