The essential microenvironmental role of oligomannoses inserted into the antigen-binding sites of lymphoma cells

Abstract

There are two mandatory features added sequentially en route to classical follicular lymphoma (FL): first the t(14;18) translocation which upregulates BCL2; second the introduction of sequence motifs into the antigen-binding sites of the B-cell receptor (BCR), where oligomannose-type glycan is added. Further processing of the glycan is blocked by complementarity-determining-region (CDR)-specific steric hindrance, leading to exposure of mannosylated Ig to the microenvironment. This allows interaction with the local lectin, DC-SIGN, expressed by tissue macrophages and follicular dendritic cells. The major function of DC-SIGN is to engage pathogens, but this is subverted by FL
cells. DC-SIGN induces tumor-specific low-level BCR signaling in FL cells and promotes membrane changes with increased adhesion to VCAM-1 via proximal kinases and actin regulators , but, in contrast to engagement by anti-Ig, avoids endocytosis and apoptosis. These interactions appear mandatory for early development of FL prior to acquisition of other accelerating mutations. BCRassociated mannosylation can be found in a subset of germinal-center B-cell-like DLBCL (GCB-DLBCL) with t(14;18), tracking those cases back to FL. This category was associated with more aggressive behavior, and both FL and transformed cases, and potentially a significant number of cases of
Burkitt’s lymphoma which also have sites for N-glycan addition, could benefit from antibodymediated blockade of the interaction with DC-SIGN.

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Identifiers

ORCID for Freda K. Stevenson: orcid.org/0000-0002-0933-5021

ORCID for Francesco Forconi: orcid.org/0000-0002-2211-1831

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