Novel secondary Ig V-H gene rearrangement and in-frame Ig heavy chain complementarity-determining region III insertion/deletion variants in de novo follicular lymphoma

Human germinal center B cell tumors retain the ability of their nontransfor med counterparts to somatically hypermutate Ig V genes by nucleotide substi tution, Among a survey of 60 primary previously untreated, clonal, follicul ar lymphomas we have identified a rare V-H rearrangement variant and two ot her 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 mi crodissection from malignant follicles. In all three cases a common clonal origin for the variants was demonstrated by complementarity-determining reg ion III nucleotide sequence homology and shared somatic mutations in germli ne encoded positions in framework region IV. The monoclonal nature of the t umors was independently confirmed by demonstrating a single t(14;18) transl ocation breakpoint in the two cases with a detectable translocation. All th e variants occurred in functional V-H rearrangements, which in two cases we re directly shown to encode functional Ab molecules, Both recombination-act ivating genes 1 and 2 were expressed in lymph node tumor cells containing t he V-H rearrangement variant, although recombination-activating gene expres sion among a panel of lymphomas was not limited to this variant.