Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma

Abstract

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 TFbinding 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.T ranscription factor (TF) activities have to be tightly controlled because their aberrant regulation alters tissue-specific gene expression programs and contributes to cancer pathogenesis. Therefore, the identification of altered TF activities in malignancies is of crucial importance to understand malignant transformation and to develop new treatment strategies. Deregulated TF activities are commonly observed in hematopoietic malignancies including human lymphomas and leukemias, and the link between structural or functional alterations in TFs and malignant transformation has been documented in various in vitro and in vivo studies (1-3). Apart from the direct modulation of cellular processes like cellular growth or cell death, alterations of the activity of even single TFs might enforce malignant transformation by switching differentiation programs and consequently altering the cellular fate of the respective cells, as exemplarily demonstrated for the B-lymphoid TF PAX5 (4, 5).Among lymphoid malignancies, one of the most prominent examples for complex patterns of deregulated TFs is classical Hodgkin lymphoma (HL), a common B cell-derived malignancy (6). Pathogenic hallmarks of the malignant Hodgkin/Reed-Sternberg (HRS) cells of HL include the constitutive activation of TFs that are only transiently activated in normal B cells, such as nuclear factor kappa B (NF-κB) or activator protein-1 (AP-1), and a profound deregulation of lineage-specific TFs such as E2A (6-8). Thus, although originating from B-lymphoid cells, HRS cells have lost their B cell-specific gene expression pattern and instead upregulate expression of genes characteristic for other hematopoietic lineages. However, the nature of the TFs initiating and maintaining HRS-specific gene expression remains poorly understood.As an unbiased approach for the identification of deregulated TF activities central to lymphoma biology, we identified HL-specific accessible chromatin regions...

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“…Importantly, the cellular infiltrate surrounding the HRS cells includes eosinophils, neutrophils and CD4 T cells which activate these receptors in a paracrine manner (Carbone et al 1995;Pinto et al 1997). A recent genomic analysis of transcription factor binding sites in HL cell lines also revealed that IRF5, aberrantly activated in HRS cells, cooperates with NF-κB to fully activate the HRS cell phenotype (Kreher et al 2014). In addition, there may be cross talk between the Notch and NF-κB pathways which further induces NF-κB activity in HL (Schwarzer et al 2012).…”

The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

“…Moreover, IRF4 transactivates Myc, and Myc activates IRF4, thus forming a positive regulatory loop, which may explain the role of IRF4 in lymphoid malignancies [128]. Although IRF5 is a mediator of death receptor-induced apoptosis [129], recent studies indicate that IRF5 promotes the proliferation of human thyroid cancer cells [130] and cooperates with NF-κB to suppress cell death of malignant Hodgkin/Reed-Sternberg cells [131]. The complex role of IRF7 during oncogenesis remains unclear.…”

New developments in the pathology of malignant lymphoma. A review of the literature published from August 2014 to October 2014

“…Kreher et al [2] looked for such areas in HL and found that areas with genes that regulate interferons are especially accessible. Subsequently, they showed that interferon regulation factor 5 (IRF5) is crucial for tumor cell survival through NF-kB activation.…”