The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma
File(s)
Published version
OA Location
Author(s)
Type
Journal Article
Abstract
Multiple myeloma is a malignancy of plasma cells initiated and driven by primary and secondary genetic events. However, myeloma plasma cell survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of the ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B-cell development in both human and murine cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma plasma cells, the interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the plasma cell lineage-defining transcription factor IRF4, thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a noncanonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.
Date Issued
2022-03-01
Date Acceptance
2021-02-02
Citation
Haematologica, 2022, 107 (3), pp.721-732
ISSN
0390-6078
Publisher
Ferrata Storti Foundation
Start Page
721
End Page
732
Journal / Book Title
Haematologica
Volume
107
Issue
3
Copyright Statement
©2022 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33596642
Subjects
DAI DLM-1/ZBP1
EXPRESSION
Hematology
IMMUNE-RESPONSES
Life Sciences & Biomedicine
NECROPTOSIS
Science & Technology
SET ENRICHMENT ANALYSIS
SIGNATURE
TARGET
TRANSCRIPTION
WEB SERVER
Z-DNA
Publication Status
Published
Coverage Spatial
Italy
Date Publish Online
2021-02-18