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

Haematologica. 2022 Mar 1;107(3):721-732. doi: 10.3324/haematol.2020.274480.

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.

MeSH terms

  • Animals
  • Cell Proliferation
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Mice
  • Multiple Myeloma* / genetics
  • Phosphorylation
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • RNA-Binding Proteins
  • ZBP1 protein, human
  • Zbp1 protein, mouse

Grant support

Funding: We acknowledge funding from Blood Cancer UK (to KP, NT, XX, and VC), KKLF (to AK), and the Imperial NIHR Biomedical Research Centre, LMS/NIHR Imperial Biomedical Research Centre Flow Cytometry Facility, Imperial BRC Genomics Facility and the MRC/LMS Sequencing Facility for support.