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

Bojan Bujisic, Aude De Gassart, Rémy Tallant, Olivier Demaria, Léa Zaffalon, Sonia Chelbi, Michel Gilliet, Francesco Bertoni and Fabio Martinon

Key Points

  • GCB DLBCLs are characterized by a defective IRE1-XBP1 pathway.

  • XBP1 expression reduces GCB DLBCL tumor growth in a mouse xenograft model.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


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.

  • Submitted September 22, 2016.
  • Accepted January 31, 2017.
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