Sir Peter MacCallum Department of Oncology - Research Publications

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    Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
    Salmon, JM ; Todorovski, I ; Stanley, KL ; Bruedigam, C ; Kearney, CJ ; Martelotto, LG ; Rossello, F ; Semple, T ; Arnau, GM ; Zethoven, M ; Bots, M ; Bjelosevic, S ; Cluse, LA ; Fraser, PJ ; Litalien, V ; Vidacs, E ; McArthur, K ; Matthews, AY ; Gressier, E ; de Weerd, NA ; Lichte, J ; Kelly, MJ ; Hogg, SJ ; Hertzog, PJ ; Kats, LM ; Vervoort, SJ ; De Carvalho, DD ; Scheu, S ; Bedoui, S ; Kile, BT ; Lane, SW ; Perkins, AC ; Wei, AH ; Dominguez, PM ; Johnstone, RW (AMER ASSOC CANCER RESEARCH, 2022-06-01)
    Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies. SIGNIFICANCE: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. This article is highlighted in the In This Issue feature, p. 1397.
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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.
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    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, 2020-06-01)
    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.