PT  - JOURNAL ARTICLE
AU  - Jessica M. Salmon
AU  - Izabela Todorovski
AU  - Stephin J. Vervoort
AU  - Kym L. Stanley
AU  - Conor J. Kearney
AU  - Luciano Martelotto
AU  - Fernando Rossello
AU  - Tim Semple
AU  - Gisela Mir-Arnau
AU  - Magnus Zethoven
AU  - Michael Bots
AU  - Eva Vidacs
AU  - Kate McArthur
AU  - Elise Gressier
AU  - Nicky de Weerd
AU  - Jens Lichte
AU  - Madison J. Kelly
AU  - Leonie Cluse
AU  - Simon J. Hogg
AU  - Paul J. Hertzog
AU  - Lev Kats
AU  - Daniel D. de Carvalho
AU  - Stefanie Scheu
AU  - Sammy Bedoui
AU  - Benjamin T. Kile
AU  - Andrew Wei
AU  - Pilar M. Dominguez
AU  - Ricky W. Johnstone
TI  - Epigenetic reprogramming of plasmacytoid dendritic cells drives type I interferon-dependent differentiation of acute myeloid leukemias for therapeutic benefit
AID  - 10.1101/2020.08.23.235499
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.23.235499
4099  - http://biorxiv.org/content/early/2020/08/24/2020.08.23.235499.short
4100  - http://biorxiv.org/content/early/2020/08/24/2020.08.23.235499.full
AB  - 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.Competing Interest StatementThe Johnstone Lab receives research support from Roche, BMS, AstraZeneca and MecRx. R.W.J is a scientific consultant and shareholder in MecRx. D.D.C received funding from Pfizer and Nektar Therapeutics and is co-founder and share-holder of DNAMx diagnostics