Sous embargo jusqu'au 30/04/2018.
Version: Author's accepted manuscript
Article: article from journal or magazin.
Impairment of both IRE1 expression and XBP1 activation is a hallmark of GCB DLBCL and contributes to tumor growth.
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
The endoplasmic reticulum kinase inositol-requiring enzyme 1 (IRE1) and its downstream target X-box-binding protein 1 (XBP1) drive B-cell differentiation toward plasma cells and have been shown to contribute to multiple myeloma development; yet, little is known of the role of this pathway in diffuse large B-cell lymphoma (DLBCL). Here, we show that in the germinal center B-cell-like (GCB) DLBCL subtype, IRE1 expression is reduced to a level that prevents XBP1 activation. Gene expression profiles indicated that, in GCB DLBCL cancer samples, expression of IRE1 messenger RNA was inversely correlated with the levels and activity of the epigenetic repressor, histone methyltransferase enhancer of zeste homolog 2 (EZH2). Correspondingly, in GCB-derived cell lines, the IRE1 promoter carried increased levels of the repressive epigenetic mark histone 3 lysine 27 trimethylation. Pharmacological inhibition of EZH2 erased those marks and restored IRE1 expression and function in vitro and in vivo. Moreover, reconstitution of the IRE1-signaling pathway, by expression of the XBP1-active form, compromised GCB DLBCL tumor growth in a mouse xenograft cancer model. These findings indicate that IRE1-XBP1 downregulation distinguishes GCB DLBCL from other DLBCL subtypes and contributes to tumor growth.
Animals, B-Lymphocytes/immunology, B-Lymphocytes/pathology, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Endoribonucleases/antagonists & inhibitors, Endoribonucleases/genetics, Endoribonucleases/immunology, Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors, Enhancer of Zeste Homolog 2 Protein/genetics, Enhancer of Zeste Homolog 2 Protein/immunology, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Germinal Center/immunology, Germinal Center/pathology, Histones/genetics, Histones/immunology, Humans, Indazoles/pharmacology, Leupeptins/pharmacology, Lymphoma, Large B-Cell, Diffuse/genetics, Lymphoma, Large B-Cell, Diffuse/immunology, Lymphoma, Large B-Cell, Diffuse/pathology, Lymphoma, Large B-Cell, Diffuse/therapy, Mice, Mice, 129 Strain, Plasma Cells/immunology, Plasma Cells/pathology, Promoter Regions, Genetic, Protein-Serine-Threonine Kinases/antagonists & inhibitors, Protein-Serine-Threonine Kinases/genetics, Protein-Serine-Threonine Kinases/immunology, Pyridones/pharmacology, RNA, Messenger/antagonists & inhibitors, RNA, Messenger/genetics, RNA, Messenger/immunology, Signal Transduction, X-Box Binding Protein 1/antagonists & inhibitors, X-Box Binding Protein 1/genetics, X-Box Binding Protein 1/immunology, Xenograft Model Antitumor Assays
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