Impaired IRE1 expression and XBP1 activation is a hallmark of GCB-DLBCL and contributes to tumor growth
Menée in vitro et in vivo sur des modèles de lymphome diffus à grandes cellules B du centre germinatif, cette étude met en évidence des mécanismes par lesquels la voie de signalisation IRE1-XBP1 régule la croissance tumorale
GCB DLBCL are characterized by a defective IRE1-XBP1 pathway.XBP1 expression reduces GCB DLBCL tumor growth in a mouse xenograft model. The endoplasmic reticulum kinase IRE1 and its downstream target XBP1 drive B cell differentiation towards plasma cells and have been shown to contribute to multiple myeloma development; yet little is known on the role of this pathway in Diffuse Large B cell Lymphoma (DLBCL). Here we show that in 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 mRNA was inversely correlated with the levels and activity of the epigenetic repressor, histone methyltransferase EZH2. Correspondingly, in GCB derived cell lines, the IRE1 promoter carried increased levels of the repressive epigenetic mark H3K27me3. 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.