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Novel Secondary Ig V_H Gene Rearrangement and In-Frame Ig Heavy Chain Complementarity-Determining Region III Insertion/Deletion Variants in De Novo Follicular Lymphoma¹

Carol B. Kobrin^2,3,*, Maurizio Bendandi^2, and Larry W. Kwak

^* Intramural Research Support Program, Science Applications International Corp.-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702; and Department of Experimental Transplantation and Immunology, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892

Human germinal center B cell tumors retain the ability of their nontransformed counterparts to somatically hypermutate Ig V genes by nucleotide substitution. Among a survey of 60 primary previously untreated, clonal, follicular lymphomas we have identified a rare V_H rearrangement variant and two other in-frame nucleotide insertion/deletion variants within complementarity-determining region III of the Ig heavy chain. The neoplastic origin of the V_H rearrangement variant was directly demonstrated in cells isolated by microdissection from malignant follicles. In all three cases a common clonal origin for the variants was demonstrated by complementarity-determining region III nucleotide sequence homology and shared somatic mutations in germline encoded positions in framework region IV. The monoclonal nature of the tumors was independently confirmed by demonstrating a single t(14;18) translocation breakpoint in the two cases with a detectable translocation. All the variants occurred in functional V_H rearrangements, which in two cases were directly shown to encode functional Ab molecules. Both recombination-activating genes 1 and 2 were expressed in lymph node tumor cells containing the V_H rearrangement variant, although recombination-activating gene expression among a panel of lymphomas was not limited to this variant.

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