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

EDELMANN, Jennifer, DOKAL, Arran D., VILVENTHRARAJA, Emma, HOLZMANN, Karlheinz, BRITTON, David, KLYMENKO, Tetyana, DÖHNER, Hartmut, CRAGG, Mark, BRAUN, Andrejs, CUTILLAS, Pedro and GRIBBEN, John G. (2021). Rituximab and obinutuzumab differentially hijack the B-cell receptor and NOTCH1 signaling pathways. iScience, 24 (2), p. 102089.

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Link to published version:: https://doi.org/10.1016/j.isci.2021.102089
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    Abstract

    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. While 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, 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.

    Item Type: Article
    Additional Information: ** Article version: AM ** From Elsevier via Jisc Publications Router ** Licence for AM version of this article starting on 20-01-2021: http://creativecommons.org/licenses/by-nc-nd/4.0/ **Journal IDs: issn 25890042 **History: issue date 22-01-2021; accepted 18-01-2021
    Identification Number: https://doi.org/10.1016/j.isci.2021.102089
    Page Range: p. 102089
    SWORD Depositor: Colin Knott
    Depositing User: Colin Knott
    Date Deposited: 10 Feb 2021 13:00
    Last Modified: 17 Mar 2021 15:16
    URI: http://shura.shu.ac.uk/id/eprint/28113

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