Deciphering the role of glycosylation in human lymphoma

• Applicant: Dr. Sebastian Scheich
• Subject Area: Hematology, Oncology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562731553

Diffuse large B cell lymphoma (DLBCL), the most common type of lymphoma, is an exceptionally heterogeneous disease that can be divided into genetic subtypes. These subtypes are characterized by distinct sets of somatic mutations, utilize specific oncogenic mechanisms, and differ in their response to therapy and prognosis. Despite recent advances in therapy, approximately 40% of DLBCL patients still suffer from relapse or refractory disease with a poor prognosis, emphasizing the need for novel treatments. The B cell receptor (BCR) is a cell surface receptor and a central signaling hub in DLBCL, which cooperates with its co-receptor CD19 to maintain oncogenic survival programs, primarily PI3 kinase and NF-κB signaling. The attachment of sugar moieties (glycosylation) is the most common posttranslational protein modification, and aberrant glycosylation is a characteristic feature of malignant cells. However, the mechanisms by which glycosylation drives oncogenic signaling in DLBCL are poorly understood. In my previous work, I investigated two focused areas of glycosylation: The role of glycosylation in oncogenic BCR signaling and the impact of glycosylation on therapy response and resistance. In my preliminary work, I identified the important role of glycosylation in two oncoproteins, BLNK and TLR9, within the oncogenic BCR pathway in aggressive lymphoma. Second, I elucidated the function of sialylation pathway genes as mediators of drug resistance and potential tumor suppressors. Third, I uncovered glycosylation pathway genes as regulators of CD19 expression, which may influence CAR T cell efficacy. Finally, I highlighted the role of the OST-B complex as a potential drug target in DLBCL. Therefore, we aim in the proposed project to unravel the underlying functional mechanisms of these four topics. Specifically, we aim to (I) mechanistically understand glycosylation of BLNK and TLR9 and functionally characterize sialylation pathway genes as mediators of drug resistance, (II) understand the function of CD19 glycosylation mediated by glucosidase and B3GNT family member enzymes and (III) target the glycosylation machinery by improving OST-B-specific compounds. In summary, the proposed project aims to deeply characterize glycosylation pathways as oncogenic drivers and find novel strategies to therapeutically exploit aberrant glycosylation in DLBCL to improve outcomes of patients with these aggressive cancers.

• DFG Programme: Emmy Noether Independent Research Groups