Tatterton, Dylan James, Newby, Maddy L., Allen, Joel D., Sale, Benjamin J., Chiodin, Giorgia, Duriez, Patrick J., Butler, John, McCann, Katy J., Scott, David W., Morin, Ryan D., Dreval, Kostiantyn, Davies, Andrew J., Bryant, Dean, Crispin, Max and Forconi, Francesco (2025) The origin, diagnosis, and prognosis of oligomannose-type diffuse large B-cell lymphoma. Blood Advances. (doi:10.1182/blood.2025029163).
Abstract
The acquisition of N-glycosylation sites occupied by oligomannose-type glycans in the immunoglobulin complementarity-determining region (CDR) is an early clonal tumor-specific identifier of follicular lymphoma (FL). CDR-located N-glycosylation sites are also acquired in germinal-center-B-cell-like diffuse large B-cell lymphomas (GCB-DLBCL), but their significance is less defined. We used RNA-seq immunoglobulin assembly to determine the frequency and CDR location of the acquired N-glycosylation sites (AGS) in two large independent DLBCL cohorts. Composition of the glycans occupying the AGS was determined using liquid chromatography-mass spectrometry and correlated with cell-of-origin, FL signature (defined by EZB phenotype or BCL2 translocation), transcript profile, and clinical outcome. CDR-located AGS were observed in 41-46% of GCB-DLBCL but were rare in other DLBCL. Only CDR-located AGS of DLBCL with an FL signature were occupied by oligomannose-type glycans. These DLBCL were termed Mann-type DLBCL. Conversely, the AGS of the other DLBCL were either non-glycosylated or occupied by complex-type glycans. Mann-type status was an independent marker of short progression-free survival and overall survival. In contrast, the other GCB-DLBCL cases, including those with an FL signature but without AGS, had the best outcomes. Mann-type DLBCL overexpressed gene-sets of cell growth, survival, and cycling, and underexpressed proinflammatory and apoptotic pathways, irrespective of concomitant MYC translocations. Acquisition of Mann-type glycans is a highly selective environmental pressure, identifying an aggressive GCB-DLBCL type with an origin related to FL. The detection of AGS in the CDR of GCB-DLBCLs with an FL signature defines Mann-type DLBCLs, refines prognosis and marks a precise tumor interaction to block early therapeutically.
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