Perspective on Immunoglobulin N-Glycosylation Status in Follicular Lymphoma: Uncovering BCR-Dependent and Independent Mechanisms Driving Subclonal Evolution.

Follicular lymphoma (FL) is a heterogeneous and incurable disease. One of the hallmark features of FL cells is the introduction of N-glycosylation (N-gly) amino acid sequence motifs into the immunoglobulin variable (IgV) region through ongoing somatic hypermutation (SHM) in the early stages of lymphoma development. These N-gly motifs, containing oligomannoses, are rarely found in healthy B cells but evidently play a crucial role in the clonal evolution and survival of FL cells in the hostile environment of germinal centers. The random nature of the ongoing SHM in FL occasionally results in the loss of productive immunoglobulin (Ig) genes or the elimination of N-gly motifs in productive genes. Such events typically lead to clonal deletion, as demonstrated by the longitudinal analysis of FL samples. However, rare N-gly-negative subclones demonstrate prolonged survival with evidence of ongoing SHM, giving rise to new N-gly-negative subclones before eventual deletion. This observation suggests the presence of specific mechanisms supporting their survival and proliferation. This perspective examines the current literature and explores whether a detailed transcriptomic and functional comparison of FL subclones characterized by different N-gly statuses, with a particular focus on N-gly-negative subclones, will lead to a comprehensive understanding of both N-gly-dependent and independent pro-survival and proliferative transcriptional signatures. Specifically, it aims to deepen our understanding of FL pathobiology and identify novel therapeutic targets for better disease management.