Sir Peter MacCallum Department of Oncology - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 2 of 2
  • Item
    No Preview Available
    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.
  • Item
    Thumbnail Image
    TET2 deficiency reprograms the germinal center B cell epigenome and silences genes linked to lymphomagenesis
    Rosikiewicz, W ; Chen, X ; Dominguez, PM ; Ghamlouch, H ; Aoufouchi, S ; Bernard, OA ; Melnick, A ; Li, S (AMER ASSOC ADVANCEMENT SCIENCE, 2020-06)
    The TET2 DNA hydroxymethyltransferase is frequently disrupted by somatic mutations in diffuse large B cell lymphomas (DLBCLs), a tumor that originates from germinal center (GC) B cells. Here, we show that TET2 deficiency leads to DNA hypermethylation of regulatory elements in GC B cells, associated with silencing of the respective genes. This hypermethylation affects the binding of transcription factors including those involved in exit from the GC reaction and involves pathways such as B cell receptor, antigen presentation, CD40, and others. Normal GC B cells manifest a typical hypomethylation signature, which is caused by AID, the enzyme that mediates somatic hypermutation. However, AID-induced demethylation is markedly impaired in TET2-deficient GC B cells, suggesting that AID epigenetic effects are partially dependent on TET2. Last, we find that TET2 mutant DLBCLs also manifest the aberrant TET2-deficient GC DNA methylation signature, suggesting that this epigenetic pattern is maintained during and contributes to lymphomagenesis.