Regulation of allelic and isotypic exclusion of human immunoglobulin (Ig) light-chain genes was studied in 113 chronic B-cell leukemias as a "single-cell" model that allowed complete analysis of each light chain allele. Our data show that monospecific Ig light chain expression is in about 90% of cases determined by ordered recombination: Igkappa gene (IGK) rearrangements, followed by IGK deletions and Iglambda gene (IGL) rearrangements, resulting in the presence of only one functional Ig light chain rearrangement. In about 10% (10 cases), 2 functional Ig light chain rearrangements (IGK/IGL or IGL/IGL, but not IGK/IGK) were identified. This might be explained by the fact that regulation of the ordered recombination process is not fully strict, particularly when the IGL locus is involved. Unfavorable somatic mutations followed by receptor editing might have contributed to this finding. Eight of these 10 cases indeed contained somatic mutations. In cases with 2 functional Ig light chain rearrangements, both alleles were transcribed, but monospecific Ig expression was still maintained. This suggests that in these cases allelelic exclusion is not regulated at the messenger RNA level but either at the level of translation or protein stability or via preferential pairing of Ig light and Ig heavy chains. Nevertheless, ordered rearrangement processes are the main determinant for monospecific Ig light chain expression.
Two polymorphisms of the human Igλ (IGL) locus have been described. The first polymorphism concerns a single, 2- or 3-fold amplification of 5.4 kb of DNA in the Cλ2-Cλ3 region. The second polymorphism is the Mcg−Ke+Oz− isotype, which has only been defined via serological analyses in Bence-Jones proteins of multiple myeloma patients and was assumed to be encoded by a polymorphic Cλ2 segment because of its high homology with the Mcg−Ke−Oz− Cλ2 isotype. It has been speculated that the Mcg−Ke+Oz− isotype might be encoded by a Cλ gene segment of the amplified Cλ2-Cλ3 region. We now unraveled both IGL gene polymorphisms. The amplification polymorphism appeared to result from a duplication, triplication, or quadruplication of a functional J-Cλ2 region and is likely to have originated from unequal crossing over of the J-Cλ2 and J-Cλ3 region via a 2.2-kb homologous repeat. The amplification polymorphism was found to result in the presence of one to five extra functional J-Cλ2 per genome regions, leading to decreased Igκ:Igλ ratios on normal peripheral blood B cells. Via sequence analysis, we demonstrated that the Mcg−Ke+Oz− isotype is encoded by a polymorphic Cλ2 segment that differs from the normal Cλ2 gene segment at a single nucleotide position. This polymorphism was identified in only 1.5% (2 of 134) of individuals without J-Cλ2 amplification polymorphism and was not found in the J-Cλ2 amplification polymorphism of 44 individuals, indicating that the two IGL gene polymorphisms are not linked.
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