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Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE198119 | GEO | 2022/03/10

REPOSITORIES: GEO

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Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML [scRNAseq DC]

Project description:Pharmacological inhibition of epigenetic enzymes can have therapeutic benefit against hematological malignancies. Apart from affecting tumor cell growth and proliferation, these epigenetic agents may mediate anti-tumor immunity. Here we discovered a novel immuno-regulatory mechanism through inhibition of histone deacetylases (HDACs). In models of AML, leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDCs) 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 activation of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, while combined treatment of panobinostat and IFN improved outcomes in mouse and human models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances anti-tumor immunity, opening the possibility of exploiting this population for immunotherapies. profiling by high throughput sequencing.

2022-03-10 | GSE198118 | GEO