Impairment of both IRE1 expression and XBP1 activation is a hallmark of GCB DLBCL and contributes to tumor growth.

Abstract

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.

• Authors: Bojan Bujisic, Aude De Gassart, Rémy Tallant, Olivier Demaria, Léa Zaffalon, Sonia Chelbi, Michel Gilliet, Francesco Bertoni, Fabio Martinon
• Journal: Blood (Blood) Vol. 129 Issue 17 Pg. 2420-2428 (04 27 2017) ISSN: 1528-0020 [Electronic] United States
• PMID: 28167662 (Publication Type: Journal Article)
• Copyright: © 2017 by The American Society of Hematology.

Chemical References

• GSK343
• Histones
• Indazoles
• Leupeptins
• Pyridones
• RNA, Messenger
• X-Box Binding Protein 1
• XBP1 protein, human
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• ERN1 protein, human
• Protein Serine-Threonine Kinases
• Endoribonucleases
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Topics

• Animals
• B-Lymphocytes (immunology, pathology)
• Cell Differentiation
• Cell Line, Tumor
• Cell Proliferation
• Endoribonucleases (antagonists & inhibitors, genetics, immunology)
• Enhancer of Zeste Homolog 2 Protein (antagonists & inhibitors, genetics, immunology)
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Germinal Center (immunology, pathology)
• Histones (genetics, immunology)
• Humans
• Indazoles (pharmacology)
• Leupeptins (pharmacology)
• Lymphoma, Large B-Cell, Diffuse (genetics, immunology, pathology, therapy)
• Mice
• Mice, 129 Strain
• Plasma Cells (immunology, pathology)
• Promoter Regions, Genetic
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, immunology)
• Pyridones (pharmacology)
• RNA, Messenger (antagonists & inhibitors, genetics, immunology)
• Signal Transduction
• X-Box Binding Protein 1 (antagonists & inhibitors, genetics, immunology)
• Xenograft Model Antitumor Assays