Impairment of both IRE1 expression and XBP1 activation is a hallmark of GCB DLBCL and contributes to tumor growth.
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 ofIRE1messenger 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, theIRE1promoter 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.
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Bojan
0000-0002-6874-7309
B
Bujisic
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Aude
0000-0002-0574-344X
A
De Gassart
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Rémy
R
Tallant
Department of Dermatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Olivier
O
Demaria
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Léa
L
Zaffalon
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Sonia
0000-0003-3465-6537
S
Chelbi
Department of Dermatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Michel
M
Gilliet
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and.|Lymphoma and Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland.
Francesco
0000-0001-5637-8983
F
Bertoni
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Fabio
0000-0002-6969-822X
F
Martinon
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000276:immunology* / Q000473:pathology; D006657:Histones / Q000235:genetics / Q000276:immunology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D057507:Mice, 129 Strain; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D011728:Pyridones / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D000071717:X-Box Binding Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
C586265:GSK343; D006657:Histones; D007191:Indazoles; D007976:Leupeptins; D011728:Pyridones; D012333:RNA, Messenger; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde