Feed-forward regulatory loop driven by IRF4 and NF-κB in adult T-cell leukemia/lymphoma. 2020

Regina Wan Ju Wong, and Tze King Tan, and Stella Amanda, and Phuong Cao Thi Ngoc, and Wei Zhong Leong, and Shi Hao Tan, and Kaori Asamitsu, and Yurina Hibi, and Ryuzo Ueda, and Takashi Okamoto, and Takashi Ishida, and Shinsuke Iida, and Takaomi Sanda
Cancer Science Institute of Singapore, National University of Singapore, Singapore.

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive hematological malignancy derived from mature CD4+ T-lymphocytes. Here, we demonstrate the transcriptional regulatory network driven by 2 oncogenic transcription factors, IRF4 and NF-κB, in ATL cells. Gene expression profiling of primary ATL samples demonstrated that the IRF4 gene was more highly expressed in ATL cells than in normal T cells. Chromatin immunoprecipitation sequencing analysis revealed that IRF4-bound regions were more frequently found in super-enhancers than in typical enhancers. NF-κB was found to co-occupy IRF4-bound regulatory elements and formed a coherent feed-forward loop to coordinately regulate genes involved in T-cell functions and development. Importantly, IRF4 and NF-κB regulated several cancer genes associated with super-enhancers in ATL cells, including MYC, CCR4, and BIRC3. Genetic inhibition of BIRC3 induced growth inhibition in ATL cells, implicating its role as a critical effector molecule downstream of the IRF4-NF-κB transcriptional network.

UI MeSH Term Description Entries
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000075747 Baculoviral IAP Repeat-Containing 3 Protein A regulator of APOPTOSIS that functions as an E3 ubiquitin protein ligase. It contains three baculoviral IAP repeats in its N-terminal half, a CARD DOMAIN, and a RING finger domain at its C-terminus. It is highly expressed in fetal lung and kidney, and adult lymphoid tissues such as spleen, thymus, and peripheral blood lymphocytes. It functions in INFLAMMATION signaling, the INNATE IMMUNE RESPONSE, cell growth and proliferation, and metastasis of tumor cells. Apoptosis Inhibitor 2,BIRC3 Protein,Baculoviral IAP Repeat Containing Protein 3,Cellular Inhibitor of Apoptosis-2,Hiap-1 Protein,IAP1 Protein,Inhibitor of Apoptosis 1 Protein,Inhibitor of Apoptosis Protein 1,c-IAP2 Protein,cIAP2 Protein,Apoptosis-2 Cellular Inhibitor,Baculoviral IAP Repeat Containing 3 Protein,Cellular Inhibitor of Apoptosis 2,Hiap 1 Protein,Inhibitor 2, Apoptosis
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015459 Leukemia-Lymphoma, Adult T-Cell Aggressive T-Cell malignancy with adult onset, caused by HUMAN T-LYMPHOTROPIC VIRUS 1. It is endemic in Japan, the Caribbean basin, Southeastern United States, Hawaii, and parts of Central and South America and sub-Saharan Africa. ATLL,HTLV I Associated T Cell Leukemia Lymphoma,HTLV-Associated Leukemia-Lymphoma,HTLV-I-Associated T-Cell Leukemia-Lymphoma,Human T Lymphotropic Virus Associated Leukemia Lymphoma,Human T Lymphotropic Virus-Associated Leukemia-Lymphoma,Human T-Cell Leukemia-Lymphoma,Leukemia Lymphoma, Adult T Cell,Leukemia Lymphoma, T Cell, Acute, HTLV I Associated,Leukemia, Adult T-Cell,Leukemia-Lymphoma, T-Cell, Acute, HTLV-I-Associated,T Cell Leukemia Lymphoma, HTLV I Associated,T Cell Leukemia, Adult,T-Cell Leukemia, Adult,T-Cell Leukemia-Lymphoma, Adult,T-Cell Leukemia-Lymphoma, HTLV-I-Associated,Adult T-Cell Leukemia,Adult T-Cell Leukemia-Lymphoma,Adult T-Cell Leukemia-Lymphomas,Adult T-Cell Leukemias,HTLV Associated Leukemia Lymphoma,HTLV-Associated Leukemia-Lymphomas,HTLV-I-Associated T-Cell Leukemia-Lymphomas,Human T Cell Leukemia Lymphoma,Human T-Cell Leukemia-Lymphomas,Leukemia, Adult T Cell,Leukemia-Lymphoma, HTLV-Associated,Leukemia-Lymphoma, HTLV-I-Associated T-Cell,Leukemia-Lymphoma, Human T-Cell,Leukemia-Lymphomas, Adult T-Cell,Leukemia-Lymphomas, HTLV-Associated,Leukemia-Lymphomas, HTLV-I-Associated T-Cell,Leukemia-Lymphomas, Human T-Cell,Leukemias, Adult T-Cell,T Cell Leukemia Lymphoma, Adult,T-Cell Leukemia-Lymphoma, Human,T-Cell Leukemia-Lymphomas, Adult,T-Cell Leukemia-Lymphomas, HTLV-I-Associated,T-Cell Leukemia-Lymphomas, Human,T-Cell Leukemias, Adult
D016328 NF-kappa B Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA. Immunoglobulin Enhancer-Binding Protein,NF-kappa B Complex,Nuclear Factor kappa B,Transcription Factor NF-kB,kappa B Enhancer Binding Protein,Ig-EBP-1,NF-kB,NF-kappaB,Nuclear Factor-Kappab,Complex, NF-kappa B,Enhancer-Binding Protein, Immunoglobulin,Factor NF-kB, Transcription,Factor-Kappab, Nuclear,Ig EBP 1,Immunoglobulin Enhancer Binding Protein,NF kB,NF kappa B Complex,NF kappaB,NF-kB, Transcription Factor,Nuclear Factor Kappab,Transcription Factor NF kB
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D049109 Cell Proliferation All of the processes involved in increasing CELL NUMBER including CELL DIVISION. Cell Growth in Number,Cellular Proliferation,Cell Multiplication,Cell Number Growth,Growth, Cell Number,Multiplication, Cell,Number Growth, Cell,Proliferation, Cell,Proliferation, Cellular

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