N-linked glycosylation of the M-protein variable region : glycoproteogenomics reveals a new layer of personalized complexity in multiple myeloma
© 2024 the author(s), published by De Gruyter, Berlin/Boston..
OBJECTIVES: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Together, glycoproteogenomics is a powerful tool to study de novo Fab N-glycosylation in plasma cell dyscrasias.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Clinical chemistry and laboratory medicine - (2024) vom: 09. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Langerhorst, Pieter [VerfasserIn] |
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| Links: |
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| Themen: |
Glycoproteogenomics |
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| Anmerkungen: |
Date Revised 14.02.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1515/cclm-2023-1189 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368221725 |
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| 100 | 1 | |a Langerhorst, Pieter |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a N-linked glycosylation of the M-protein variable region |b glycoproteogenomics reveals a new layer of personalized complexity in multiple myeloma |
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| 520 | |a © 2024 the author(s), published by De Gruyter, Berlin/Boston. | ||
| 520 | |a OBJECTIVES: 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 | ||
| 520 | |a METHODS: 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 | ||
| 520 | |a RESULTS: 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 | ||
| 520 | |a CONCLUSIONS: Together, glycoproteogenomics is a powerful tool to study de novo Fab N-glycosylation in plasma cell dyscrasias | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a M-protein | |
| 650 | 4 | |a N-glycosylation | |
| 650 | 4 | |a glycoproteogenomics | |
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| 700 | 1 | |a Baerenfaenger, Melissa |e verfasserin |4 aut | |
| 700 | 1 | |a Kulkarni, Purva |e verfasserin |4 aut | |
| 700 | 1 | |a Nadal, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Wijnands, Charissa |e verfasserin |4 aut | |
| 700 | 1 | |a Post, Merel A |e verfasserin |4 aut | |
| 700 | 1 | |a Noori, Somayya |e verfasserin |4 aut | |
| 700 | 1 | |a vanDuijn, Martijn M |e verfasserin |4 aut | |
| 700 | 1 | |a Joosten, Irma |e verfasserin |4 aut | |
| 700 | 1 | |a Dejoie, Thomas |e verfasserin |4 aut | |
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| 700 | 1 | |a Lefeber, Dirk J |e verfasserin |4 aut | |
| 700 | 1 | |a Wessels, Hans J C T |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobs, Joannes F M |e verfasserin |4 aut | |
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