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- Title
N-linked glycosylation of the M-protein variable region: glycoproteogenomics reveals a new layer of personalized complexity in multiple myeloma.
- Authors
Langerhorst, Pieter; Baerenfaenger, Melissa; Kulkarni, Purva; Nadal, Simon; Wijnands, Charissa; Post, Merel A.; Noori, Somayya; vanDuijn, Martijn M.; Joosten, Irma; Dejoie, Thomas; van Gool, Alain J.; Gloerich, Jolein; Lefeber, Dirk J.; Wessels, Hans J.C.T.; Jacobs, Joannes F.M.
- Abstract
Multiple myeloma (MM) is a plasma cell malignancy characterized by a monoclonal expansion of plasma cells that secrete a characteristic M-protein. This M-protein is crucial for diagnosis and monitoring of MM in the blood of patients. Recent evidence has emerged suggesting that N-glycosylation of the M-protein variable (Fab) region contributes to M-protein pathogenicity, and that it is a risk factor for disease progression of plasma cell disorders. Current methodologies lack the specificity to provide a site-specific glycoprofile of the Fab regions of M-proteins. Here, we introduce a novel glycoproteogenomics method that allows detailed M-protein glycoprofiling by integrating patient specific Fab region sequences (genomics) with glycoprofiling by glycoproteomics. Glycoproteogenomics was used for the detailed analysis of de novo N-glycosylation sites of M-proteins. First, Genomic analysis of the M-protein variable region was used to identify de novo N-glycosylation sites. Subsequently glycopeptide analysis with LC-MS/MS was used for detailed analysis of the M-protein glycan sites. Genomic analysis uncovered a more than two-fold increase in the Fab Light Chain N-glycosylation of M-proteins of patients with Multiple Myeloma compared to Fab Light Chain N-glycosylation of polyclonal antibodies from healthy individuals. Subsequent glycoproteogenomics analysis of 41 patients enrolled in the IFM 2009 clinical trial revealed that the majority of the Fab N-glycosylation sites were fully occupied with complex type glycans, distinguishable from Fc region glycans due to high levels of sialylation, fucosylation and bisecting structures. Together, glycoproteogenomics is a powerful tool to study de novo Fab N-glycosylation in plasma cell dyscrasias.
- Subjects
MULTIPLE myeloma; PLASMA cell diseases; PLASMA cells; DISEASE risk factors; GLYCOSYLATION; CD38 antigen; GLYCANS
- Publication
Clinical Chemistry & Laboratory Medicine, 2024, Vol 62, Issue 8, p1626
- ISSN
1434-6621
- Publication type
Article
- DOI
10.1515/cclm-2023-1189