Altered N-Linked Glycosylation in Follicular Lymphoma and Chronic Lymphocytic Leukemia: Involvement in Pathogenesis and Potential Therapeutic Targeting

Abstract

B-cell antigen receptor (BCR) expression is indispensable for survival of most B-cell malignancies. In follicular lymphoma (FL), N-linked glycosylation sites are introduced in the immunoglobulin (Ig) variable region genes. Oligosaccharides added to the acquired sites are unusually of the high-mannose type. These glycans interact with mannose-specific lectins, especially with dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). Lectin binding to FL triggers persistent activating signals, suggesting that lectins within the tumor microenvironment promote cell survival and proliferation. Insertion of N-glycosylation sites in Ig variable region genes has been detected in other germinal center-associated lymphomas, specifically in subsets of diffuse large B-cell lymphomas and Burkitt’s lymphomas, suggesting involvement of altered glycans in pathogenesis of these malignancies as well. Furthermore, the BCR in chronic lymphocytic leukemia (CLL) carries high-mannose oligosaccharides, albeit in the heavy chain constant rather than variable region. The high expression level of the unique glycoform, particularly in the more aggressive unmutated CLL subset, suggests a functional significance for this glycan in CLL. As lectin interaction with the BCR is critical for FL and probably for some other lymphomas, targeting this interaction is considered to be an interesting therapeutic strategy. Reagents for blockade of lectin–BCR interaction may include antibodies against high-mannose glycans and mannose-based oligosaccharide mimics or non-carbohydrate glycomimetics. Moreover, as this interaction triggers signaling pathways similar to those demonstrated for BCR engagement by antigen, BCR signal transduction inhibitors may emerge as effective therapeutics for lectin-driven malignancies.

Unraveling Tumor Heterogeneity in an Apparently Monolithic Disease: BCL2 and Other Players in the Genetic Landscape of Nodal Follicular Lymphoma

“…Candidate molecules for this interaction include C-type lectins expressed by macrophages and dendritic cells, which have been proposed as possible targets for new therapeutic strategies. In this regard, promising agents include both antibodies against high-mannose glycans and mannose-based oligosaccharide mimics or non-carbohydrate glycomimetics that act as competitive inhibitors of lectin–glycoprotein interactions are currently being developed against human immunodeficiency virus, since envelope glycans of this virus are almost entirely of the oligomannose type ( 12 ). Further studies are needed to validate the efficacy of these therapeutics in the treatment of FL.…”

Follicular Lymphoma Microenvironment: An Intricate Network Ready for Therapeutic Intervention

“…We have recently demonstrated that FL-FDC niche promotes, via the secretion of CCL2 and CSF-1, monocyte recruitment, differentiation, and polarization towards an M2-like pro-tumoral phenotype, as seen in FL patient biopsies [5], favoring angiogenesis, dissemination, and immunosuppression [22]. Moreover, macrophages express C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) that binds to mannosylated BCR, activating B cell survival independently of Ag [23][24][25]. In addition, monocyte/macrophages trans-present IL-15 to B cells in the FL niche and cooperate with T-cell-derived CD40L to promote IL-15-dependent B-cell proliferation [26].…”

A Comparison of Immunoglobulin Variable Region N-Linked Glycosylation in Healthy Donors, Autoimmune Disease and Lymphoma

“…In contrast to the highly sialylated variable domain glycans in RA, AAV, and IgG4-RD patients, FL variable domain glycans were reported to be rich in high-mannose structures ( Table 1) (91,92,103). Such glycans were solely observed at sites which were newly acquired through somatic hypermutation.…”