SELECTIVITY OF ANTIGEN RECEPTORS IN SPLENIC MARGINAL-ZONE LYMPHOMA: FURTHER EVIDENCE FROM THE IMMUNOGLOBULIN LIGHT CHAIN GENE REPERTOIRE

Sborník

We recently demonstrated that over 30% of cases with splenic marginal-zone lymphoma (SMZL) express B cell receptors (BcRs) that utilize a single polymorphic variant of the IGHV1-2 gene (IGHV1-2*04). These IGHV1-2*04 receptors carry distinctive antigen-binding sites and also exhibit a low impact of somatic hypermutation (SHM), albeit with preferential targeting of certain positions of the VH domain. These molecular features argue for selection by (super)antigenic element(s) in the pathogenesis of at least a subset of SMZL; in addition, they indicate heavy chain dominance in the clonogenic IG receptors of SMZL. That notwithstanding, the possibility that immunoglobulin (IG) light chains might also play an important role in SMZL ontogeny needs to be investigated, in view of their relevant role in normal, autoreactive and malignant B-cell clones. In order to address this issue, we systematically explored the IG light chain gene repertoire in 114 productive VJ rearrangements from 108 SMZL cases.Seventeen functional IGKV genes were identified in 83 IGKV-J rearrangements; IGKV3- 20 was the most frequent gene (20/83 cases, 24%), followed by IGKV4-1 (13/83, 15.7%) and IGKV1-39, IGKV1-5, IGKV1-8/1D-8 (10 cases each, 12%). Collectively, the aforementioned IGKV genes accounted for 76% of all IGKV-J rearrangements. Fourteen functional IGLV genes were identified in 31 IGLV-J rearrangements; IGLV2-14 predominated by far (10/31, 32%). Accordingly, the IG light chain gene repertoire of SMZL is remarkably biased, in analogy to the corresponding IG heavy chain gene repertoire.Based on the percentage of IGKV/IGLV gene identity to the germline (GI), 21/114 sequences (18.5%) were assigned to a truly unmutated subgroup (100% GI), whereas the remaining sequences (93/114, 81.5%) exhibited some impact of SHM activity, ranging from minimal to pronounced. Sequences with 97-99.9% GI were classified as borderline/minimally mutated (n=61, 53.5%), whereas those with <97% GI as significantly mutated (n=32, 28%). Overall, the distribution of IG light chain sequences with regards to SHM status recapitulated what we observed in SMZL heavy chains, implicating a similar impact of SHM on both heavy and light chains.Focusing on the subgroup of 17 IGHV1-2*04 cases with available IG light chain sequence information (19 productive rearrangements), we obtained clear evidence for biased usage of two light chain genes, namely IGKV3-20*01 (6/19 cases, 32%) and IGKV1-8*01 (5/19, 26%). In these pairs, as for the heavy chain (IGHV1-2*04), also the light chain genes (IGKV3-20*01 or IGKV1-8*01) were borderline/minimally mutated. Interestingly, in the case of IGKV3-20*01 sequences, shared (stereotyped) somatic mutations were identified, with IMGT codons CDR1-37 and FR3-66 emerging as hotspots for recurrent, conservative amino acid changes.In conclusion, the present study indicates a complementary role of light chains in shaping BcR specificity and provides further evidence for the highly selective nature of the IG repertoire in SMZL. The restricted molecular features of the IG light chains in the IGHV1-2*04 subgroup may reflect an antigen-driven immune pathway to lymphoma development and further support our recent claims for the existence of distinct subtypes of SMZL defined by immunogenetic analysis.

Haematologica, 2012; 97(s1):  245