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Antigen Selection in Human Lymphomagenesis¹

Division of Oncology, Department of Medicine, Stanford University Medical Center, Stanford, California 94305 [D. W. B., T. T. C., R. L.], and Memorial Sloan-Kettering Cancer Center, Division of Hematologic Oncology/Lymphoma Service, New York, New York 10021 [A. D. Z.]

Although surface immunoglobulin plays a central role in the differentiation and growth of normal B-cells, its role in the growth of human B-cell malignancies is largely a matter of conjecture. Human follicular lymphomas are attractive systems to study in part because they are clones of cells sharing many similarities with germinal center B-cells which are critically dependent on antigen selection for survival. Nucleotide sequence information was determined for the immunoglobulin heavy chain variable genes expressed by two cases of follicular lymphoma. In addition, the germ line variable gene counterparts were also cloned and sequenced from biopsy material obtained from both of these patients. Numerous mutations from germ line were present in the variable genes from both of these cases, many of which accumulated during expansion and growth of these lymphomas. Moreover, the mutations that accumulated during tumor expansion were distributed in a manner that almost certainly was dependent on positive selection presumably mediated by contact with an antigen. These data indicate that antigen selection is probably important for the growth and clonal evolution of follicular lymphomas.