Genome regulation in cancers: Critical role of IRF4
Abnormal activities of transcription factors and chromatin modifiers play critical roles in shaping the aberrant gene expression programs that define cancer cells. Identifying the target genes and signaling pathways controlled by such factors are an important step in designing targeted therapies against cancers.
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. We now 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, such as the NF-κB pathway, as a target of IRF4 in ABC-DLBCL. Furthermore, we implicate another transcription factor (SPIB) as an IRF4 partner, critical for lymphoma cells. Overall, our results suggest therapeutic potential for targeting IRF4 activity and its interactions in aggressive mature B-cell lymphoma.
N. C. Tolga EMRE, PhD: short biography
Dr. N. C. Tolga Emre got his bachelor’s degree in 1997 from Molecular Biology and Genetics (MBG) in Boğaziçi University, and then master’s degree from MBG at Bilkent University, Ankara with Rengül Çetin-Atalay’s mentorship. In 1999, he joined the Graduate Group in Biology at the University of Pennsylvania in Philadelphia, PA, USA. After a period of coursework, laboratory teaching and rotations, he has joined for doctoral thesis studies Shelley Berger’s lab in the Gene Expression and Regulation Program at the neighboring Wistar Institute. There, he has studied the role of histone modifications in genome regulation, in particular histone deubiquitylation in gene silencing. For postdoctoral research he has worked in Louis Staudt's group at Lymphoid Malignancies Section of National Cancer Institute, National Institutes of Health (NIH) in Bethesda, MD, USA where he has applied genome-wide expression and localization techniques (such as expression microarrays and ChIP-Seq) to analyze gene regulatory pathways mediated through histone modifications and key transcription factors, in order to identify potential therapeutic targets in blood cancers. In 2011, Dr. Emre has joined Boğaziçi MBG, and his group at the Laboratory of Genome Regulation there has since been doing research on gene regulatory mechanisms, especially in cancers.