Abstract LB-248: IRF4 as a critical regulator and potential therapeutic target in ABC type diffuse large B-cell lymphoma

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Interferon regulatory factor 4 (IRF4) is a transcriptional regulator with crucial roles in the development of lymphocytes and implicated in malignant transformation. Recently, we have demonstrated that cell lines derived from cancers of plasma cell origin (i.e., multiple myeloma) are addicted to an anomalous gene expression program driven by the wild-type IRF4. Here, we show that an aggressive malignancy of mature B-cells, the activated B-cell-like type of diffuse large B-cell lymphoma (ABC-DLBCL), also requires IRF4 for survival. With an integrative analysis of genome-wide IRF4 localization (ChIP-Seq) assays and gene expression profiling, we identify IRF4 target genes in ABC-DLBCL as members of diverse pathways related to B-cell biology and oncogenesis, largely distinct from the IRF4 targets in multiple myeloma cells. For instance, we identify CARD11, an adaptor in the NF-κB pathway, as a target of IRF4 in ABC-DLBCL, and confirm this by cell-based reporter assays. This novel regulatory mechanism complements the established aspects of ABC-DLBCL pathobiology, where NF-κB pathway is constitutively active and indispensable, and drives IRF4 expression. Furthermore, we find enrichment for a composite ETS-IRF DNA motif in IRF4 binding regions in ABC-DLBCL, suggesting cooperative activity between IRF4 and ETS transcription factor(s). Supporting this, we demonstrate through complementation assays that critical amino acids on IRF4 and the ETS factor SPIB, notably those residues important for their interaction, are essential for the survival of ABC-DLBCL, but not multiple myeloma cells. Taken together we show that ABC-DLBCL cells are addicted to the transcription factor IRF4, in part through a positive feedback mechanism involving CARD11, NF-κB, and IRF4. In addition, our results suggest therapeutic potential for targeting the IRF4-ETS interaction interface in ABC-DLBCL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-248. doi:10.1158/1538-7445.AM2011-LB-248