Studies on the clonal origin of multiple myeloma. Use of individually specific (idiotype) antibodies to trace the oncogenic event to its earliest point of expression in B-cell differentiation.
IgA myeloma proteins of kappa- and lambda-types were isolated from two patients. These were used to produce and purify anti-idiotype antibodies of both broad (myeloma-related) and narrow (individual myeloma) specificities. The anti-idiotype antibodies were conjugated with fluorochromes and used as immunofluorescent probes to trace in the patients clonal expansion at different levels of B-cell differentiation. Our results (a) confirm that B lymphocyte precursors in IgA plasma-cell myelomas are involved in the malignant process, (b) show that B lymphocytes of the malignant clone include those expressing each of the major heavy-chain isotypes, mu, delta, gamma, and alpha, and (c) provide strong circumstantial evidence that pre-B-cell members of the malignant clone are also increased in frequency. T cells expressing idiotypic determinants were not detected. These findings argue that the initial oncogenic event may occur in a B-stem cell and is not influenced through stimulation by antigen. An interesting association was the increased frequency of related clones of B lymphocytes as detected by their reactivity with anti-idiotype antibodies of broad specificity. Neither plasma cell nor pre-B-cell members of these related clones were increased in frequency. Anti-idiotype antibodies or helper T cells reactive with myeloma-related idiotypes could be responsible for this phenomenon. We discuss other implications of these findings and speculate that all of the various phenotypes of B-lineage malignancies may result from oncogenic processes affecting stem cell targets.
D000912:Antibodies, Neoplasm / Q000276:immunology*; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000032:analysis; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation; D000939:Epitopes; D006801:Humans; D007070:Immunoglobulin A; D007130:Immunoglobulin Idiotypes; D009101:Multiple Myeloma / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D009194:Myeloma Proteins / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D000939:Epitopes; D007070:Immunoglobulin A; D007130:Immunoglobulin Idiotypes; D009194:Myeloma Proteins