title: Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma.
abstract: 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.
authors: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892; lstaudt@mail.nih.gov lrui@medicine.wisc.edu.|Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.|Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors: Lixin
authors: L
authors: Rui
authors: Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.|Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors: Amanda C
authors: AC
authors: Drennan
authors: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
authors: Michele
authors: M
authors: Ceribelli
authors: Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.|Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors: Fen
authors: F
authors: Zhu
authors: Biometric Research Branch, DCTD, National Cancer Institute, NIH, Bethesda, MD 20892.
authors: George W
authors: GW
authors: Wright
authors: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
authors: Da Wei
authors: DW
authors: Huang
authors: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079.
authors: Wenming
authors: W
authors: Xiao
authors: Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.|Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors: Yangguang
authors: Y
authors: Li
authors: Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.|Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors: Kreg M
authors: KM
authors: Grindle
authors: Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.|Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors: Li
authors: L
authors: Lu
authors: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
authors: Daniel J
authors: DJ
authors: Hodson
authors: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
authors: Arthur L
authors: AL
authors: Shaffer
authors: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
authors: Hong
authors: H
authors: Zhao
authors: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
authors: Weihong
authors: W
authors: Xu
authors: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
authors: Yandan
authors: Y
authors: Yang
authors: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892; lstaudt@mail.nih.gov lrui@medicine.wisc.edu.
authors: Louis M
authors: LM
authors: Staudt
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507904:JAK1 protein, human; D053613:Janus Kinase 1
keywords: JAK1; epigenetics; histone modification; lymphoma; oncogene