biostudies-literatureSalmon JMGerman Research FoundationCancer Council VictoriaNHMRC EL1 FellowshipCure Cancer AustraliaCanada Research Chairs NHMRCVictorian Cancer Agency FellowshipDutch Research Council (NWO)NHMRC Principal Research FellowshipCanadian Institute of Health ResearchCIHR1560-1579https://www.ebi.ac.uk/biostudies/studies/S-EPMC9355625biostudies-literatureUnknown12(6)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 tyCancer discoveryEpigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML.PMC9355625019.161LW.017GNT11783391051444GRK2158MCRF150032706509151484301659861113577201512MSH360794-228629FDN 1484301063008SCHE692/6-1PJT 165986454569Litalien VArnau GMPerkins ACZethoven MKearney CJRossello FCluse LAMartelotto LGde Weerd NAHogg SJFraser PJVidacs EWei AHDe Carvalho DDKile BTKelly MJHertzog PJKats LMBjelosevic SMcArthur KMatthews AYSalmon JMLane SWScheu SVervoort SJJohnstone RWTodorovski IBots MStanley KLBruedigam CGressier EBedoui SDominguez PMSemple TLichte JfalseEpigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML.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 ty2022-01-01T00:00:00Z2022 Jun2026-05-09T22:16:04.429Z2025-04-04T20:20:30.314ZS-EPMC93556253531199710.1158/2159-8290.CD-20-1145