Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Bedoui, Sammy × Author: Johnstone, Ricky × Type: Preprint ×

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    Epigenetic reprogramming of plasmacytoid dendritic cells drives type I interferon-dependent differentiation of acute myeloid leukemias for therapeutic benefit
    Salmon, J ; Todorovski, I ; Vervoort, S ; Stanley, K ; Kearney, C ; Martelotto, L ; Rossello, F ; Semple, T ; Mir-Arnau, G ; Zethoven, M ; Bots, M ; Vidacs, E ; McArthur, K ; Gressier, E ; de Weerd, N ; Lichte, J ; Kelly, M ; Cluse, L ; Hogg, S ; Hertzog, P ; Kats, L ; de Carvalho, D ; Scheu, S ; Bedoui, S ; Kile, B ; Wei, A ; Dominguez, P ; Johnstone, R ( 2020-08-24)
    Pharmacological inhibition of epigenetic enzymes can have therapeutic benefit, particularly against hematological malignancies. While these agents can affect tumor cell growth and proliferation, recent studies have demonstrated that pharmacological de-regulation of epigenetic modifiers may additionally mediate anti-tumor immune responses. Here we discovered a novel mechanism of immune regulation through the inhibition of histone deacetylases (HDACs). In a genetically engineered model of t(8;21) AML, leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor panobinostat required activation of the type I interferon (IFN) signaling pathway. Plasmacytoid dendritic cells (pDCs) were identified as the cells producing type I IFN in response to panobinostat, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated activation of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, while combined treatment of panobinostat and recombinant IFNα improved therapeutic outcomes. These discoveries offer a new therapeutic approach for t(8;21) AML and demonstrate that epigenetic rewiring of pDCs enhances anti-tumor immunity, opening the possibility of exploiting this cell type as a new target for immunotherapy.