The Origin, Diagnosis, and Prognosis of Oligomannose-Type Diffuse Large B Cell Lymphoma

Tatterton, D. J.; Newby, M. L.; Allen, J. D.; Sale, B. J.; Chiodin, G.; Duriez, P. J.; Butler, J.; McCann, K. J.; Scott, D. W.; Morin, R. D.; Dreval, K.; Davies, A. S.; Bryant, D. J.; Crispin, M.; Forconi, F.

doi:10.1101/2025.03.11.642396

bioRxiv · 10.1101/2025.03.11.642396

The Origin, Diagnosis, and Prognosis of Oligomannose-Type Diffuse Large B Cell Lymphoma

Tatterton, D. J.·Newby, M. L.·Allen, J. D.·Sale, B. J.·Chiodin, G.·Duriez, P. J.·Butler, J.·McCann, K. J.·Scott, D. W.·Morin, R. D.·Dreval, K.·Davies, A. S.·Bryant, D. J.·Crispin, M.·Forconi, F.

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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 the most aggressive GCB-DLBCL with an origin related to FL. The detection of AGS in the CDR of GCB-DLBCLs with a BCL2 translocation defines Mann-type DLBCLs, refines prognosis and marks a precise tumor interaction to block early therapeutically. Key pointsO_LIAcquisition of Mann-type glycans is a tumor-specific environmental pressure identifying the most aggressive GCB-DLBCL with an origin related to FL. C_LIO_LIMann-type DLBCL can be diagnosed by the concomitant detection of AGS in the CDR and a BCL2 translocation. C_LI

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Tatterton, D. J., Newby, M. L., Allen, J. D., Sale, B. J., Chiodin, G., Duriez, P. J., Butler, J., McCann, K. J., Scott, D. W., Morin, R. D., Dreval, K., Davies, A. S., Bryant, D. J., Crispin, M., Forconi, F.. 2025-03-13. The Origin, Diagnosis, and Prognosis of Oligomannose-Type Diffuse Large B Cell Lymphoma. https://doi.org/10.1101/2025.03.11.642396

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