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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review IRF4 (interferon regulatory factor 4) Silvia Rasi, Gianluca Gaidano Division of Hematology, Department of Clinical and Experimental Medicine & Center of Biotechnologies for Applied Medical Research, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy (SR, GG) Published in Atlas Database: January 2009 Online updated version : http://AtlasGeneticsOncology.org/Genes/IRF4ID231ch6p25.html DOI: 10.4267/2042/44637 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology Transcription Identity Length of the transcript is 5314 bp. Coding sequence: CDS 114-1469. mRNA is expressed at high levels in lymphoid tissues, in skin and in tonsils. Other names: IRF-4; NF-EM5; LSIRF (lymphocytespecific interferon regulatory factor); MUM1 (multiple myeloma oncogene 1) HGNC (Hugo): IRF4 Location: 6p25.3 Local order: IRF4 is located on chromosome 6 at the telomeric extremity of the short arm, and lies between the DUSP22 (dual specificity phosphatase 22) and EXOC2 (exocyst complex component 2) genes. Note: IRF4 belongs to the IRF (interferon regulatory factors) family of genes, that are known to be active in the control of B-cell proliferation and differentiation. Protein Description Protein length: 451 amino acids. Calculated molecular weight of 51.8 kDa. There are 2 different isoforms produced by alternative splicing (Q15306-1/Q15306-2). Expression IRF4 protein is expressed in lymphoid cells and it is tissue specific. In normal lymphoid tissues, IRF4 protein is detected mainly in plasma cells and in a small number of germinal-center B cells. In addition, IRF4 is expressed in a small percentage of T cells and in most perifollicular CD30-positive cells. Expression of IRF4 is not induced by interferons. DNA/RNA Description Gene of 19.4 Kb with 9 exons and 8 introns. Exon 1, the 5' part of exon 2 and the 3' part of exon 9 are non coding. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(12) 941 IRF4 (interferon regulatory factor 4) Rasi S, Gaidano G Translocations involving 14q32 are found in a significant fraction of patients, and include t(6;14)(p25;q32). Hybrid/Mutated gene The translocation juxtaposes the IgH locus to the IRF4 gene. Oncogenesis The chromosomal translocation t(6;14)(p25;q32) in MM may cause transcriptional activation of the IRF4 proto-oncogene. As a result of the translocation, IRF4 is overexpressed, and this event may contribute to tumorigenesis in vitro. Localisation Nucleus. Function IRF4 is a lymphoid-specific transcription factor that plays crucial roles in the development and in the functions of immune cells. This gene controls B-cell proliferation and differentiation, and proliferation of mitogen-activated T cells. IRF4 is a transcriptional activator and binds to the interferon-stimulated response element (ISRE) of the MHC class I promoter. Also, IRF4 binds to the immunoglobulin lambda light chain enhancer, together with PU.1 and probably plays a role in ISRE-targeted signal transduction mechanisms specific of lymphoid cells. IRF4 negatively regulates Toll-like receptor (TLR) signaling by competing with IRF5, and inhibits proinflammatory cytokine production. Moreover, IRF4 positively regulates the biosynthetic processes of interleukin IL-2, IL-4, IL-10, and IL-13. B-cell chronic lymphocytic leukemia (BCLL) Disease B-CLL is the most common form of leukemia in the Western world. The disease presents a heterogeneous clinical course, with some patients surviving for many years without requiring any specific therapy and others progressing rapidly despite aggressive treatment. Prognosis It is not yet clear if the presence of IRF4 expression in B-CLL represents a favourable or unfavourable prognostic marker. In fact, previous studies have demonstrated a variable expression of IRF4 in B-CLL patients and a conflicting prognostic significance. Homology IRF4 shows homology to other members of the IRF family, in particular IRF1, IRF2, IRF3, IRF5, IRF6, IRF7, and IRF8. IRF4 contains one tryptophan pentad repeat DNAbinding domain. Mutations Adult T-cell leukemia (ATL) Note Mutations in the distal and proximal sites of the GCrich sequence of the IRF4 promoter cause a reduction of 62 and 81%, activity in the IRF4 promoter, respectively. Disease ATL is an aggressive leukemia of CD4+ T lymphocytes and is also associated with a neurological demyelinating disease, tropical spastic paraparesis (TSP) or HTLV-1 Associated Myelopathies (HAM). The human T cell leukemia/lymphotrophic virus-1 (HTLV-1) is the aetiologic agent of ATL, and the disease is geographically localized to regions of the world where HTLV infection is endemic. IRF4 was shown to be highly expressed in cells derived from patients with ATL and in HTLV-1 infected cell lines. IRF4 expression increases during the progression of ATL, with IRF4 expression levels highest during the late acute phase of ATL. Oncogenesis IRF4 is involved in the pathogenesis of ATL through its positive effect on the cell cycle. IRF4 transcriptional downregulation would lead to an overall decrease in DNA repair and a subsequent increase in cellular mutations, thus contributing to cellular transformation. Implicated in Multiple myeloma (MM) Disease The proto-oncogene IRF4 is deregulated in MM with translocation t(6;14)(p25;q32). IRF4 is also deregulated in B-cell non Hodgkin lymphoma (NHL) and in particular in diffuse large B-cell lymphoma (DLBCL). MM is a malignant monoclonal plasma cell proliferation that has a complex molecular aetiology with several subgroups defined by gene expression profiling and recurrent chromosomal translocations. IRF4 inhibition is toxic to myeloma cell lines, regardless of the precise transforming oncogenic mechanism. MYC is a direct target of IRF4 gene in activated B-cells and in mMM. IRF4 is itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. Cytogenetics t(6;14)(p25;q32) --> IRF4 - IgH. Possibly other translocations of IRF4 with unidentified partner chromosomes have been identified. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(12) Primary effusion lymphoma (PEL) Disease PEL is a clinico-pathological category of B-cell nonHodgkin's lymphoma (NHL) based on the infection of the tumour clone by human herpesvirus type-8/Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV). PEL preferentially develops in immunodeficient patients and 942 IRF4 (interferon regulatory factor 4) Rasi S, Gaidano G Falini B, Mason DY. Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. Blood. 2002 Jan 15;99(2):409-26 displays a marked preference for liquid growth in the serous body cavities in the absence of clinically identifiable tumour masses. Although PEL belongs to the B-cell lineage, the overwhelming majority of cases exhibit a non-B, non-T phenotype, lacking expression of surface immunoglobulins (Ig) and common B cell associated. Oncogenesis IRF4 expression in PEL is a result of the stage of differentiation of the tumour clone. At present, the role of IRF4 expression in PEL growth is yet unknown, although it has been documented that IRF4 is capable of inducing transformation in experimental cellular systems. Ito M, Iida S, Inagaki H, Tsuboi K, Komatsu H, Yamaguchi M, Nakamura N, Suzuki R, Seto M, Nakamura S, Morishima Y, Ueda R. MUM1/IRF4 expression is an unfavorable prognostic factor in B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Jpn J Cancer Res. 2002 Jun;93(6):685-94 Mamane Y, Grandvaux N, Hernandez E, Sharma S, Innocente SA, Lee JM, Azimi N, Lin R, Hiscott J. Repression of IRF-4 target genes in human T cell leukemia virus-1 infection. Oncogene. 2002 Oct 3;21(44):6751-65 Nishiya N, Yamamoto K, Imaizumi Y, Kohno T, Matsuyama T. Identification of a novel GC-rich binding protein that binds to an indispensable element for constitutive IRF-4 promoter activity in B cells. Mol Immunol. 2004 Jul;41(9):855-61 References Grossman A, Mittrücker HW, Nicholl J, Suzuki A, Chung S, Antonio L, Suggs S, Sutherland GR, Siderovski DP, Mak TW. Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25. Genomics. 1996 Oct 15;37(2):229-33 Honma K, Udono H, Kohno T, Yamamoto K, Ogawa A, Takemori T, Kumatori A, Suzuki S, Matsuyama T, Yui K. Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16001-6 Iida S, Rao PH, Butler M, Corradini P, Boccadoro M, Klein B, Chaganti RS, Dalla-Favera R. Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nat Genet. 1997 Oct;17(2):226-30 Negishi H, Ohba Y, Yanai H, Takaoka A, Honma K, Yui K, Matsuyama T, Taniguchi T, Honda K. Negative regulation of Toll-like-receptor signaling by IRF-4. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15989-94 Mittrücker HW, Matsuyama T, Grossman A, Kündig TM, Potter J, Shahinian A, Wakeham A, Patterson B, Ohashi PS, Mak TW. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science. 1997 Jan 24;275(5299):540-3 Ortmann CA, Burchert A, Hölzle K, Nitsche A, Wittig B, Neubauer A, Schmidt M. Down-regulation of interferon regulatory factor 4 gene expression in leukemic cells due to hypermethylation of CpG motifs in the promoter region. Nucleic Acids Res. 2005;33(21):6895-905 Tsuboi K, Iida S, Inagaki H, Kato M, Hayami Y, Hanamura I, Miura K, Harada S, Kikuchi M, Komatsu H, Banno S, Wakita A, Nakamura S, Eimoto T, Ueda R. MUM1/IRF4 expression as a frequent event in mature lymphoid malignancies. Leukemia. 2000 Mar;14(3):449-56 Shaffer AL, Emre NC, Lamy L, Ngo VN, Wright G, Xiao W, Powell J, Dave S, Yu X, Zhao H, Zeng Y, Chen B, Epstein J, Staudt LM. IRF4 addiction in multiple myeloma. Nature. 2008 Jul 10;454(7201):226-31 Chang CC, Lorek J, Sabath DE, Li Y, Chitambar CR, Logan B, Kampalath B, Cleveland RP. Expression of MUM1/IRF4 correlates with clinical outcome in patients with B-cell chronic lymphocytic leukemia. Blood. 2002 Dec 15;100(13):4671-5 This article should be referenced as such: Atlas Genet Cytogenet Oncol Haematol. 2009; 13(12) Rasi S, Gaidano G. IRF4 (interferon regulatory factor 4). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(12):941-943. 943