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

Ponnusamy, K.; Tzioni, M. M.; Begum, M.; Robinson, M. E.; Caputo, V. S.; Katsarou, A.; Trasanidis, N.; Xiao, X.; Kostopoulos, I. V.; Iskander, D.; Roberts, I.; Trivedi, P.; Auner, H. W.; Naresh, K.; Chaidos, A.; Karadimitris, A.

doi:10.1101/2020.06.17.157107

bioRxiv · 10.1101/2020.06.17.157107

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

Ponnusamy, K.·Tzioni, M. M.·Begum, M.·Robinson, M. E.·Caputo, V. S.·Katsarou, A.·Trasanidis, N.·Xiao, X.·Kostopoulos, I. V.·Iskander, D.·Roberts, I.·Trivedi, P.·Auner, H. W.·Naresh, K.·Chaidos, A.·Karadimitris, A.

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Abstract

ZBP1 is an inducible, non-constitutively expressed cellular nucleic acid sensor that triggers type I interferon (IFN) responses via phosphorylation and activation of the transcription factor (TF) IRF3 by TBK1. However, the role of the ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively and constitutively expressed in late B cell development and it is required for optimal T cell-dependent humoral immune responses. In the plasma cell (PC) cancer multiple myeloma, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. Notably, rather than IFN type I response genes, IRF3 directly activates, in part through co-operation with the PC lineage-defining TF IRF4, cell cycle genes thus promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. These data expand our knowledge of the role of cellular immune sensors in cancer biology.

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Ponnusamy, K., Tzioni, M. M., Begum, M., Robinson, M. E., Caputo, V. S., Katsarou, A., Trasanidis, N., Xiao, X., Kostopoulos, I. V., Iskander, D., Roberts, I., Trivedi, P., Auner, H. W., Naresh, K., Chaidos, A., Karadimitris, A.. 2020-06-18. The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma. https://doi.org/10.1101/2020.06.17.157107

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