Τίτλος:
The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 non-canonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology. © 2022 Ferrata Storti Foundation.
Συγγραφείς:
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.
Περιοδικό:
Haematologica-the hematology journal
Εκδότης:
Ferrata Storti Foundation
Λέξεις-κλειδιά:
aluminum potassium sulfate; DNA binding protein; doxycycline; interferon regulatory factor 3; keyhole limpet hemocyanin; unclassified drug; z DNA binding protein 1, animal cell; animal model; Article; cell cycle; cell growth; cell maturation; cell proliferation; cell survival; chromatin immunoprecipitation; coimmunoprecipitation; controlled study; flow cytometry; gene; gene expression; gene overexpression; genetic transfection; high throughput sequencing; human; human cell; humoral immunity; immunization; immunoblotting; memory cell; microarray analysis; mouse; multiple myeloma; nonhuman; protein expression; real time polymerase chain reaction; RNA sequence; RNA sequencing; TBK1 gene; upregulation
DOI:
10.3324/haematol.2020.274480
