Ig gene diversification and selection in follicular lymphoma, diffuse large B cell lymphoma and primary central nervous system lymphoma revealed by lineage tree and mutation analyses

Abstract

Follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL) and primary central nervous system lymphoma are B cell malignancies. FL and DLBCL have a germinal center origin. We have applied mutational analyses and a novel algorithm for quantifying shape properties of mutational lineage trees to investigate the nature of the diversification, somatic hypermutation and selection processes that affect B cell clones in these malignancies and reveal whether they differ from normal responses. Lineage tree analysis demonstrated higher diversification and mutations per cell in the lymphoma clones. This was caused solely by the longer diversification times of the malignant clones, as their recent diversification processes were similar to those of normal responses, implying similar mutation frequencies. Since previous analyses of antigen-driven selection were shown to yield false positives, we performed a corrected analysis of replacement and silent mutation patterns, which revealed selection against replacement mutations in the framework regions, responsible for the structural integrity of the B cell receptor, but not for positive selection for replacements in the complementary determining regions. Most replacements, however, were neutral or conservative, suggesting that if at all selection operates in these malignancies it is for structural B cell receptor integrity but not for antigen binding.

Lectins from opportunistic bacteria interact with acquired variable-region glycans of surface immunoglobulin in follicular lymphoma

“…However, a recent study described negative selection against replacement mutations in the framework regions but no positive selection of replacement mutations in the CDRs, indicating a selection to maintain the structural integrity of the FL BCRs rather than a positive selection for antigen recognition. 53 Our unpublished data suggest that novel N-glycosylation sites appeared as one of the first events within the genealogical BCR trees and that SHM eradicated potential N-glycosylation sites in only around 1% of the FL cases (Scherer Florian et al, manuscript in preparation). Together, these observations suggest a positive selection for the acquisition of N-glycosylation sites in FL.…”

DC-SIGN–expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma

“…In addition, whereas FL cells carry evidence of intraclonal evolution related to the ongoing somatic hypermutation process, mutational analysis of immunoglobulin variable regions reveals a counterselection of mutations affecting BCR structural integrity. 3,4 Finally, resistance to anti-idiotype therapy was shown to rely on mutations of the targeted immunoglobulin sequence rather than on loss of BCR expression. 5,6 Study of the FL BCR signaling profile highlighted a lack of constitutive activation together with a strong interindividual variability in both magnitude and kinetic of the signal.…”

Automated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles

“…Previous studies have, for example: revealed the association of certain germline genotypes with susceptibility to such diseases as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) (5,6); found correlations of age with a reduced Ig clonal diversity and less intense response to immune challenge (7,8); found overly expanded clones in cases of lymphoma (9,10); and discovered convergent Ig evolution across subjects in response to certain immune challenges (11,12). These repertoire-sequencing (Rep-Seq) studies have benefitted from improvements in sequencing technologies, which allow for the generation of millions of reads per run (13).…”