The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma

Journal article

Ponnusamy, K., Tzioni, M. M., Begum, M., Robinson, M. E., Caputo, V., Katsarou, A., Trasanidis, N., Xiao, X., Kostopoulos, I. V., Iskander, D., Roberts, I., Trivedi, P., Auner, H. W., Naresh, K., Chaidos, A. and Karadimitris, A. (2021). The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma. Haematologica. https://doi.org/10.3324/haematol.2020.274480
AuthorsPonnusamy, K., Tzioni, M. M., Begum, M., Robinson, M. E., Caputo, V., Katsarou, A., Trasanidis, N., Xiao, X., Kostopoulos, I. V., Iskander, D., Roberts, I., Trivedi, P., Auner, H. W., Naresh, K., Chaidos, A. and Karadimitris, A.
Abstract

Multiple myeloma is a malignancy of plasma cells (PC) initiated and driven by primary and secondary genetic events. Nevertheless, myeloma PC 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 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 mouse cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma PC, 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 PC lineage-defining transcription factor IRF4, and 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 non-canonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.

Year2021
JournalHaematologica
PublisherEuropean Hematology Association
Ferrata Storti Foundation
ISSN0390-6078
Digital Object Identifier (DOI)https://doi.org/10.3324/haematol.2020.274480
Publication dates
Online18 Feb 2021
Publication process dates
Accepted18 Feb 2021
Deposited17 Jun 2021
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License
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Open
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