Abstract
Abstract Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin's lymphoma, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Dysreguation of genes related with B cell differentiation contributes to the tumorigenesis of DLBCL; the. Jumonji domain containing-3 (JMJD3), a histone 3 Lys27 (H3K27) demethylase, plays a known role in antigen-driven B-cell differentiation in GCB cells. But the mechanism of JMJD3 in DLBCL progression remains poorly uncerstood. Here we show that JMJD3 exerts an anti-apoptotic effect in both ABC and GCB subtypes of DLBCL. The downregulation of JMJD3 increased apoptosis among DLBCL cells. In the ABC subtype, JMJD3 regulates the interferon regulatory factor 4 (IRF4) in a demethylase activity-dependent fashion. Interestingly, IRF4 could reciprocally regulate the expression of JMJD3, forming a positive feedback regulation loop. The expression of IRF4 was sufficient to rescue survival induced by the JMJD3 suppression selectively in the ABC type. In the GCB subtype, JMJD3-mediated survival was dependent upon increased expression of the anti-apoptotic protein BCL2. Treatment with JMJD3 siRNA could also reduce tumor volume concordant with increased apoptosis of DLBCL cells. Our results demonstrate a previously unrecognized role of JMJD3 in the survival of both the ABC and GCB subtype of DLBCL and provide molecular insight into the mechanisms by which the JMJD3-IRF4 or JMJD3-BCL2 axis controls this process. Key words: DLBCL, apoptosis, JMJD3, IRF4, BCL2 Citation Format: Yan Zhang. JMJD3 promotes the survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 348. doi:10.1158/1538-7445.AM2014-348
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