Kreher Stephan, Bouhlel M Amine, Cauchy Pierre, Lamprecht Björn, Li Shuang, Grau Michael, Hummel Franziska, Köchert Karl, Anagnostopoulos Ioannis, Jöhrens Korinna, Hummel Michael, Hiscott John, Wenzel Sören-Sebastian, Lenz Peter, Schneider Markus, Küppers Ralf, Scheidereit Claus, Giefing Maciej, Siebert Reiner, Rajewsky Klaus, Lenz Georg, Cockerill Peter N, Janz Martin, Dörken Bernd, Bonifer Constanze, Mathas Stephan
Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, United Kingdom;
Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4513-22. doi: 10.1073/pnas.1406985111. Epub 2014 Oct 6.
Deregulated transcription factor (TF) activities are commonly observed in hematopoietic malignancies. Understanding tumorigenesis therefore requires determining the function and hierarchical role of individual TFs. To identify TFs central to lymphomagenesis, we identified lymphoma type-specific accessible chromatin by global mapping of DNaseI hypersensitive sites and analyzed enriched TF-binding motifs in these regions. Applying this unbiased approach to classical Hodgkin lymphoma (HL), a common B-cell-derived lymphoma with a complex pattern of deregulated TFs, we discovered interferon regulatory factor (IRF) sites among the top enriched motifs. High-level expression of the proinflammatory TF IRF5 was specific to HL cells and crucial for their survival. Furthermore, IRF5 initiated a regulatory cascade in human non-Hodgkin B-cell lines and primary murine B cells by inducing the TF AP-1 and cooperating with NF-κB to activate essential characteristic features of HL. Our strategy efficiently identified a lymphoma type-specific key regulator and uncovered a tumor promoting role of IRF5.
转录因子（TF）活性失调在造血系统恶性肿瘤中普遍存在。因此，了解肿瘤发生需要确定单个TF的功能和层级作用。为了鉴定淋巴瘤发生的核心TF，我们通过全基因组DNaseI超敏位点图谱确定了淋巴瘤类型特异性的可及染色质，并分析了这些区域中富集的TF结合基序。将这种无偏倚的方法应用于经典型霍奇金淋巴瘤（HL），这是一种常见的B细胞来源淋巴瘤，其TF失调模式复杂，我们在最富集的基序中发现了干扰素调节因子（IRF）位点。促炎TF IRF5的高水平表达是HL细胞特有的，对其存活至关重要。此外，IRF5通过诱导TF AP-1并与NF-κB协同激活HL的基本特征，在人非霍奇金B细胞系和原代小鼠B细胞中启动了一个调节级联反应。我们的策略有效地鉴定了一种淋巴瘤类型特异性的关键调节因子，并揭示了IRF5的促肿瘤作用。
