Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

Abstract

We performed an immunogenetic analysis of 345 IGHV --IGHD --IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; 12.8%; 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele *04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2*04 peaked at 31%. The IGHV1-2*04 rearrangements carried significantly longer complementaritydetermining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2*04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97 --99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2*04 allele.

Selection of antigen receptors in splenic marginal-zone lymphoma: further support from the analysis of the immunoglobulin light-chain gene repertoire

“…1 The IGHV1-2*04 BcRs in SMZL are characterized by long complementarity-determining region-3 (CDR3) and exhibit a low impact of somatic hypermutation (SHM), leading to limited changes, which cluster in certain positions of the VH domain. Altogether, these features argue for selection by antigen in the pathogenesis of SMZL and suggest heavy chain (HC) dominance in the clonogenic immunoglobulin (IG) receptors of SMZL.…”

“…Altogether, these features argue for selection by antigen in the pathogenesis of SMZL and suggest heavy chain (HC) dominance in the clonogenic immunoglobulin (IG) receptors of SMZL. 1 That notwithstanding, the possibility that IG light chains (IG LC) might also have an important role in SMZL ontogeny exists and needs to be investigated. This is supported by studies demonstrating that IG LCs may be critically implicated in recognition of and selection by antigen.…”

“…7 Finally, marked LC gene repertoire biases exist in various B-cell lymphomas, strongly indicating that LCs can contribute significantly toward shaping antigen reactivity of the clonotypic BcRs. 8 In order to gain insight into the role of IG LCs in SMZL we explored the IG LC gene repertoire in 107 SMZL cases diagnosed as described previously 1 and carrying at least one productive LC rearrangement. The analysis was performed on spleen specimens or peripheral blood samples as described previously.…”

“…All sequences, including 41 sequences previously reported from our groups, 9,10 were evaluated following the novel strategy detailed in our recent publications. 1,8 Overall, 113 productive IG LC rearrangements were amplified from 107 cases. Six cases carried two productive IG LC rearrangements along with a single productive HC rearrangement, effectively ruling out the possibility of biclonal population.…”

“…Hence, overall, the distribution of IG LC sequences with regards to SHM status recapitulated what we observed in SMZL HCs. 1 Assessment of paired heavy and light variable domains (VH and VK/VL) with regards to SHM status in 100 of the 107 cases with available data revealed two general patterns (Supplementary Table 3): (i) both VH and VK/VL with a similar impact of SHM: 61 cases (6 cases with truly unmutated VH þ VK/VL, 30 cases with borderline/minimally mutated VH þ VK/VL, 25 cases with significantly mutated VH þ VK/VL); (ii) VH and VK/VL with discordant mutational status, that is assigned to a different SHM subgroup; in this latter category, 33 cases carried more heavily mutated VH versus VK/VL domains, whereas the opposite was observed in the remaining 6 cases, which carried more heavily mutated VK/VL versus VH domains.…”