文章基本信息

标题：Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma
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作者：Lixin Rui ; Amanda C. Drennan ; Michele Ceribelli 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：E7260-E7267
DOI：10.1073/pnas.1610970113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAutocrine cytokine signaling in cancer can activate members of the Janus kinase (JAK) family, which are generally thought to act by phosphorylating STAT family transcription factors. We report here that JAK1 mediates autocrine IL-6 and IL-10 cytokine signaling in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) by a noncanonical epigenetic regulatory mechanism involving phosphorylation of histone H3 on tyrosine 41. We have identified target genes that are activated in ABC DLBCL by this epigenetic mechanism. Knowledge of these epigenetic targets led to our demonstration that JAK1 inhibitors synergize with inhibitors of active B cell receptor signaling in ABC DLBCL, suggesting a new therapeutic strategy for this subtype of DLBCL, which is the most difficult to cure with current therapy. Janus kinases (JAKs) classically signal by activating STAT transcription factors but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated B-cell (ABC) subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin, or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells. Whereas STAT3 contributed to the survival of ABC DLBCL cell lines, forced STAT3 activity could not protect these cells from death following JAK1 inhibition, suggesting epigenetic JAK1 action. JAK1 regulated the expression of nearly 3,000 genes in ABC DLBCL cells, and the chromatin surrounding many of these genes was modified by H3Y41-P marks that were diminished by JAK1 inhibition. These JAK1 epigenetic target genes encode important regulators of ABC DLBCL proliferation and survival, including IRF4, MYD88, and MYC. A small molecule JAK1 inhibitor cooperated with the BTK inhibitor ibrutinib in reducing IRF4 levels and acted synergistically to kill ABC DLBCL cells, suggesting that this combination should be evaluated in clinical trials.
关键词：JAK1 ; epigenetics ; histone modification ; lymphoma ; oncogene