Abstract
Immunoglobulin kappa (IGK) locus rearrangements were analyzed in parallel on cDNA/genomic DNA in 188 kappa- and 103 lambda-chronic lymphocytic leukemia (CLL) cases. IGKV-KDE and IGKJ-C-intron-KDE rearrangements were also analyzed on genomic DNA. In kappa-CLL, only 3 of 188 cases carried double in-frame IGKV-J transcripts: in such cases, the possibility that leukemic cells expressed more than one kappa chain cannot be excluded. Twenty-eight kappa-CLL cases also carried nonexpressed (nontranscribed and/or out-of-frame) IGKV-J rearrangements. Taking IGKV-J, IGKV-KDE, and IGKJ-C-intron-KDE rearrangements together, 38% of kappa-CLL cases carried biallelic IGK locus rearrangements. In lambda-CLL, 69 IGKV-J rearrangements were detected in 64 of 103 cases (62%); 24 rearrangements (38.2%) were in-frame. Four cases carried in-frame IGKV-J transcripts but retained monotypic light-chain expression, suggesting posttranscriptional regulation of allelic exclusion. In all, taking IGKV-J, IGKV-KDE, and IGKJ-C-intron-KDE rearrangements together, 97% of lambda-CLL cases had at least 1 rearranged IGK allele, in keeping with normal cells. IG repertoire comparisons in kappa- versus lambda-CLL revealed that CLL precursor cells tried many rearrangements on the same IGK allele before they became lambda producers. Thirteen of 28 and 26 of 69 non-expressed sequences in, respectively, kappa- or lambda-CLL had < 100% homology to germline. This finding might be considered as evidence for secondary rearrangements occurring after the onset of somatic hypermutation, at least in some cases. The inactivation of potentially functional IGKV-J joints by secondary rearrangements indicates active receptor editing in CLL and provides further evidence for the role of antigen in CLL immunopathogenesis.
Highlights
The most widely accepted model for regulation of isotype exclusion at immunoglobulin (Ig) light-chain loci proposes that immunoglobulin λ (IGL) rearrangements occur only after nonfunctional immunoglobulin κ (IGK) rearrangements [1]
Patient Samples Peripheral blood (PB) samples were collected from 291 chronic lymphocytic leukemia (CLL) patients
Transcripts along with in-frame IGLV-J transcripts but still retained monotypic Ig expression: in these cases allelic exclusion was probably regulated at the posttranscriptional level
Summary
The most widely accepted model for regulation of isotype exclusion at immunoglobulin (Ig) light-chain loci (ordered model) proposes that immunoglobulin λ (IGL) rearrangements occur only after nonfunctional immunoglobulin κ (IGK) rearrangements [1]. Sequencing analysis was successful for 22 of 24 IGKV-KDE rearrangements and revealed frequent usage of the IGKV1D-43 gene (4 of 22 cases; 18.1%), which was rare in either the expressed or nonexpressed CLL repertoire (Supplemental Table).
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