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

Rituximab and obinutuzumab differentially hijack the B-cell receptor and NOTCH1 signaling pathways
Rituximab and obinutuzumab differentially hijack the B-cell receptor and NOTCH1 signaling pathways
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.
cancer, immunology, systems biology: proteomics
Edelmann, Jennifer
573e8a7e-4e3b-4007-b2fd-3a136cbe5baa
Dokal, Arran D.
bdf951d9-133a-413d-9c6e-10d7093eb011
Vilventhraraja, Emma
f794d50c-bd2c-4f18-8a2f-302eaf557ff2
Holzmann, Karlheinz
f6b5d2aa-e5a1-42d6-8deb-ba095d98d767
Britton, David
07f61418-7770-483d-aaa9-c1693be103cf
Klymenko, Tetyana
38eb6eba-6d27-4a04-a2c7-fa7d885a0a7a
Döhner, Hartmut
6e7be004-744b-484d-ae35-32f5941c3b96
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Braun, Andrejs
a40f851b-1cd7-4ce7-8c25-832e38950f52
Cutillas, Pedro
e097269e-e672-4e73-a11c-06d162b5fa24
Gribben, John G.
086dd67d-a2d9-4d2c-97d6-8e345eb84142
Edelmann, Jennifer
573e8a7e-4e3b-4007-b2fd-3a136cbe5baa
Dokal, Arran D.
bdf951d9-133a-413d-9c6e-10d7093eb011
Vilventhraraja, Emma
f794d50c-bd2c-4f18-8a2f-302eaf557ff2
Holzmann, Karlheinz
f6b5d2aa-e5a1-42d6-8deb-ba095d98d767
Britton, David
07f61418-7770-483d-aaa9-c1693be103cf
Klymenko, Tetyana
38eb6eba-6d27-4a04-a2c7-fa7d885a0a7a
Döhner, Hartmut
6e7be004-744b-484d-ae35-32f5941c3b96
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Braun, Andrejs
a40f851b-1cd7-4ce7-8c25-832e38950f52
Cutillas, Pedro
e097269e-e672-4e73-a11c-06d162b5fa24
Gribben, John G.
086dd67d-a2d9-4d2c-97d6-8e345eb84142

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), [102089]. (doi:10.1016/j.isci.2021.102089).

Record type: Article

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. 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.

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Accepted/In Press date: 18 January 2021
e-pub ahead of print date: 22 January 2021
Keywords: cancer, immunology, systems biology: proteomics

Identifiers

Local EPrints ID: 446918
URI: http://eprints.soton.ac.uk/id/eprint/446918
PURE UUID: 6708cde8-5186-4ea9-99b8-22fa8cae4548
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 26 Feb 2021 17:31
Last modified: 26 Nov 2021 02:40

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Contributors

Author: Jennifer Edelmann
Author: Arran D. Dokal
Author: Emma Vilventhraraja
Author: Karlheinz Holzmann
Author: David Britton
Author: Tetyana Klymenko
Author: Hartmut Döhner
Author: Mark Cragg ORCID iD
Author: Andrejs Braun
Author: Pedro Cutillas
Author: John G. Gribben

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