Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features
Epigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasm...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Society of Hematology
2020
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| _version_ | 1797082335100796928 |
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| author | Roos-Weil, D Giacopelli, B Armand, M Della-Valle, V Ghamlouch, H Decaudin, C Metzner, M Lu, J Le Garff-Tavernier, M Leblond, V Vyas, P Zenz, T Nguyen-Khac, F Bernard, OA Oakes, CC |
| author_facet | Roos-Weil, D Giacopelli, B Armand, M Della-Valle, V Ghamlouch, H Decaudin, C Metzner, M Lu, J Le Garff-Tavernier, M Leblond, V Vyas, P Zenz, T Nguyen-Khac, F Bernard, OA Oakes, CC |
| author_sort | Roos-Weil, D |
| collection | OXFORD |
| description | Epigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasmacytic phenotypes. Here, we integrated genome-wide DNA methylation, transcriptome, mutation, and phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B-cell subsets. Patients naturally segregate into 2 groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and PC-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development captured tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3, and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic, and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P = .015), deletion 13q (P = .006), splenomegaly (P = .02), and thrombocytopenia (P = .004), whereas PC-like WM harbored more deletion 6q (P = .012), gain 6p (P = .033), had increased frequencies of IGHV3 genes (P = .002), CD38 expression (P = 4.1e-5), and plasmacytic differentiation features (P = .008). Together, our findings illustrate a novel approach to subclassify WM patients using DNA methylation and reveal divergent molecular signatures among WM patients. |
| first_indexed | 2024-03-07T01:26:43Z |
| format | Journal article |
| id | oxford-uuid:9239b8ad-7c59-4dca-8127-cd3a68f6edb9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:26:43Z |
| publishDate | 2020 |
| publisher | American Society of Hematology |
| record_format | dspace |
| spelling | oxford-uuid:9239b8ad-7c59-4dca-8127-cd3a68f6edb92022-03-26T23:24:00ZIdentification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell featuresJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9239b8ad-7c59-4dca-8127-cd3a68f6edb9EnglishSymplectic ElementsAmerican Society of Hematology2020Roos-Weil, DGiacopelli, BArmand, MDella-Valle, VGhamlouch, HDecaudin, CMetzner, MLu, JLe Garff-Tavernier, MLeblond, VVyas, PZenz, TNguyen-Khac, FBernard, OAOakes, CCEpigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasmacytic phenotypes. Here, we integrated genome-wide DNA methylation, transcriptome, mutation, and phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B-cell subsets. Patients naturally segregate into 2 groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and PC-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development captured tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3, and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic, and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P = .015), deletion 13q (P = .006), splenomegaly (P = .02), and thrombocytopenia (P = .004), whereas PC-like WM harbored more deletion 6q (P = .012), gain 6p (P = .033), had increased frequencies of IGHV3 genes (P = .002), CD38 expression (P = 4.1e-5), and plasmacytic differentiation features (P = .008). Together, our findings illustrate a novel approach to subclassify WM patients using DNA methylation and reveal divergent molecular signatures among WM patients. |
| spellingShingle | Roos-Weil, D Giacopelli, B Armand, M Della-Valle, V Ghamlouch, H Decaudin, C Metzner, M Lu, J Le Garff-Tavernier, M Leblond, V Vyas, P Zenz, T Nguyen-Khac, F Bernard, OA Oakes, CC Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features |
| title | Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features |
| title_full | Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features |
| title_fullStr | Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features |
| title_full_unstemmed | Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features |
| title_short | Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features |
| title_sort | identification of 2 dna methylation subtypes of waldenstrom macroglobulinemia with plasma and memory b cell features |
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