Insights into the regulation of immunoglobulin light chain gene rearrangements via analysis of the κ light chain locus in λ myeloma

Abstract

Accumulating evidence indicates that B cells may undergo sequential rearrangements at the light chain loci, despite already expressing light chain receptors. This phenomenon may occur in the bone marrow and, perhaps, in germinal centers. As immunoglobulin (Ig)κ light chains usually rearrange before Igλ light chains, we analysed, by polymerase chain reaction, the Igκ locus of bone marrow mononuclear cells from 29 patients with Igλ myeloma to identify earlier recombinations in marrow plasma cells. The results demonstrated that Igκ alleles were inactivated via the kappa-deleting element, presumably prior to Vκ-Jκ rearrangement, in many cases. Eighteen alleles (16 myeloma clones, 55%) showed Vκ-Jκ rearrangements, with increased utilization of 5′ distant Vκ and 3′ distant Jκ gene segments (Jκ4, 56%), an indication of multiple sequential rearrangements. In-frame, potentially functional Vκ-Jκ rearrangements were found in approximately one-third of available rearrangements (as expected by chance), each one in different myeloma clones: three were germline encoded, while one had several nucleotide substitutions, suggesting inactivation after the onset of somatic hypermutation. Three of four potentially functional Vκ-Jκ rearrangements involved Vκ4-1, a segment considered to be associated with autoimmunity. These findings provide insights into the regulation of light chain rearrangements and support the view that B cells may occasionally undergo sequential light chain rearrangements after the onset of somatic hypermutation.