Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways

Summary: The anti-CD20 monoclonal antibodies rituximab and obinutuzumab differ in their mechanisms of action, with obinutuzumab evoking greater direct B cell death. To characterize the signaling processes responsible for improved B cell killing by obinutuzumab, we undertook a phosphoproteomics appro...

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Main Authors: Jennifer Edelmann, Arran D. Dokal, Emma Vilventhraraja, Karlheinz Holzmann, David Britton, Tetyana Klymenko, Hartmut Döhner, Mark Cragg, Andrejs Braun, Pedro Cutillas, John G. Gribben
Format: Article
Language:English
Published: Elsevier 2021-02-01
Series:iScience
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2589004221000572
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spelling doaj-65cb49ad086b46e487c814941865f4352021-02-21T04:35:25ZengElsevieriScience2589-00422021-02-01242102089Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathwaysJennifer Edelmann0Arran D. Dokal1Emma Vilventhraraja2Karlheinz Holzmann3David Britton4Tetyana Klymenko5Hartmut Döhner6Mark Cragg7Andrejs Braun8Pedro Cutillas9John G. Gribben10Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Department of Internal Medicine III, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany; Corresponding authorCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Kinomica Limited, Biohub Alderley Park, Alderley Edge, Macclesfield, Cheshire, SK10 4TG, UKCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UKCenter for Clinical Research, Genomics Core Facility, Ulm University, Helmholtzstr. 8/1, 89081 Ulm, GermanyCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Kinomica Limited, Biohub Alderley Park, Alderley Edge, Macclesfield, Cheshire, SK10 4TG, UKCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Sheffield Hallam University, City Campus, Howard Street, Sheffield, S1 1WB, UKDepartment of Internal Medicine III, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, GermanyAntibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, SO16 6YD, UKCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UKCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Kinomica Limited, Biohub Alderley Park, Alderley Edge, Macclesfield, Cheshire, SK10 4TG, UKCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UKSummary: The anti-CD20 monoclonal antibodies rituximab and obinutuzumab differ in their mechanisms of action, with obinutuzumab evoking greater direct B cell death. To characterize the signaling processes responsible for improved B cell killing by obinutuzumab, we undertook a phosphoproteomics approach and demonstrate that rituximab and obinutuzumab differentially activate pathways downstream of the B cell receptor. Although both antibodies induce strong ERK and MYC activation sufficient to promote cell-cycle arrest and B cell death, obinutuzumab exceeds rituximab in supporting apoptosis induction by means of aberrant SYK phosphorylation. In contrast, rituximab elicits stronger anti-apoptotic signals by activating AKT, by impairing pro-apoptotic BAD, and by releasing membrane-bound NOTCH1 to up-regulate pro-survival target genes. As a consequence, rituximab appears to reinforce BCL2-mediated apoptosis resistance. The unexpected complexity and differences by which rituximab and obinutuzumab interfere with signaling pathways essential for lymphoma pathogenesis and treatment provide important impetus to optimize and personalize the application of different anti-CD20 treatments.http://www.sciencedirect.com/science/article/pii/S2589004221000572immunologysystems biology: proteomicscancer
collection DOAJ
language English
format Article
sources DOAJ
author Jennifer Edelmann
Arran D. Dokal
Emma Vilventhraraja
Karlheinz Holzmann
David Britton
Tetyana Klymenko
Hartmut Döhner
Mark Cragg
Andrejs Braun
Pedro Cutillas
John G. Gribben
spellingShingle Jennifer Edelmann
Arran D. Dokal
Emma Vilventhraraja
Karlheinz Holzmann
David Britton
Tetyana Klymenko
Hartmut Döhner
Mark Cragg
Andrejs Braun
Pedro Cutillas
John G. Gribben
Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways
iScience
immunology
systems biology: proteomics
cancer
author_facet Jennifer Edelmann
Arran D. Dokal
Emma Vilventhraraja
Karlheinz Holzmann
David Britton
Tetyana Klymenko
Hartmut Döhner
Mark Cragg
Andrejs Braun
Pedro Cutillas
John G. Gribben
author_sort Jennifer Edelmann
title Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways
title_short Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways
title_full Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways
title_fullStr Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways
title_full_unstemmed Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways
title_sort rituximab and obinutuzumab differentially hijack the b cell receptor and notch1 signaling pathways
publisher Elsevier
series iScience
issn 2589-0042
publishDate 2021-02-01
description Summary: The anti-CD20 monoclonal antibodies rituximab and obinutuzumab differ in their mechanisms of action, with obinutuzumab evoking greater direct B cell death. To characterize the signaling processes responsible for improved B cell killing by obinutuzumab, we undertook a phosphoproteomics approach and demonstrate that rituximab and obinutuzumab differentially activate pathways downstream of the B cell receptor. Although both antibodies induce strong ERK and MYC activation sufficient to promote cell-cycle arrest and B cell death, obinutuzumab exceeds rituximab in supporting apoptosis induction by means of aberrant SYK phosphorylation. In contrast, rituximab elicits stronger anti-apoptotic signals by activating AKT, by impairing pro-apoptotic BAD, and by releasing membrane-bound NOTCH1 to up-regulate pro-survival target genes. As a consequence, rituximab appears to reinforce BCL2-mediated apoptosis resistance. The unexpected complexity and differences by which rituximab and obinutuzumab interfere with signaling pathways essential for lymphoma pathogenesis and treatment provide important impetus to optimize and personalize the application of different anti-CD20 treatments.
topic immunology
systems biology: proteomics
cancer
url http://www.sciencedirect.com/science/article/pii/S2589004221000572
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