Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML [RNAseq WT tumor cells]. Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML [RNAseq WT tumor cells]

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. Overall design: Following three days of treatment with panobinostat or vehicle, leukemia tumor cells (GFP+) were sorted, using propidium iodide (PI) as a viability marker (3 replicates per group).

表观遗传酶的药理学抑制可对血液系统恶性肿瘤（hematological malignancies）产生治疗获益。除影响肿瘤细胞的生长与增殖外，此类表观遗传药物还可介导抗肿瘤免疫应答。本研究通过抑制组蛋白去乙酰化酶（histone deacetylases，HDACs），发现了一种全新的免疫调控机制。在急性髓系白血病（acute myeloid leukemia，AML）模型中，组蛋白去乙酰化酶抑制剂帕比司他（panobinostat）所介导的白血病细胞分化与治疗获益，依赖于I型干扰素（type I interferon，IFN）通路的激活。经帕比司他处理后，浆细胞样树突状细胞（plasmacytoid dendritic cells，pDCs）可产生I型干扰素，该过程伴随干扰素基因的转录激活，且这些基因位点的H3K27乙酰化水平显著升高。剔除浆细胞样树突状细胞可消除帕比司他介导的白血病细胞内I型干扰素信号通路激活，并削弱其治疗效果；而联合应用帕比司他与干扰素α（IFNα）可改善小鼠及人类模型中的治疗结局。上述研究发现为急性髓系白血病提供了全新的治疗策略，并证实对浆细胞样树突状细胞进行表观遗传重编程可增强抗肿瘤免疫，为利用此类细胞开发免疫治疗手段开辟了可能。高通量测序分析。整体实验设计：以碘化丙啶（propidium iodide，PI）作为细胞存活标记物，对经帕比司他或溶媒处理3天的白血病肿瘤细胞（GFP+）进行分选，每组设置3个生物学重复。