文章基本信息

标题：Schlafen 11 expression in human acute leukemia cells with gain-of-function mutations in the interferon-JAK signaling pathway
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作者：Yasuhisa Murai ; Ukhyun Jo ; Junko Murai 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：10
页码：1-20
DOI：10.1016/j.isci.2021.103173
语种：English
出版社：Elsevier
摘要：SummarySchlafen11 (SLFN11) is referred to as interferon (IFN)-inducible. Based on cancer genomic databases, we identified human acute myeloid and lymphoblastic leukemia cells with gain-of-function mutations in the Janus kinase (JAK) family as exhibiting high SLFN11 expression. In these cells, the clinical JAK inhibitors cerdulatinib, ruxolitinib, and tofacitinib reduced SLFN11 expression, but IFN did not further induce SLFN11 despite phosphorylated STAT1. We provide evidence that suppression of SLFN11 by JAK inhibitors is caused by inactivation of the non-canonical IFN pathway controlled by AKT and ERK. Accordingly, the AKT and ERK inhibitors MK-2206 and SCH77284 suppressed SLFN11 expression. Both also suppressed the E26 transformation-specific (ETS)-family genes ETS-1 and FLI-1 that act as transcription factors for SLFN11. Moreover, SLFN11 expression was inhibited by the ETS inhibitor TK216. Our study reveals that SLFN11 expression is regulated via the JAK, AKT and ERK, and ETS axis. Pharmacological suppression of SLFN11 warrants future studies.Graphical abstractDisplay OmittedHighlights•SLFN11 expression is high in leukemia and confers response to DNA targeted agents•SLFN11 expression is driven by the innate immune IFN-JAK signaling pathway•Leukemia cell lines with JAK-GOF-mutations express high SLFN11 downstream from the AKT/ERK-ETS pathway•JAK and ETS inhibitors suppress SLFN11 expressionCell biology; Immunology; Molecular biology