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IRF4 (interferon regulatory factor 4)

Identity

Other namesIRF-4
NF-EM5
LSIRF (lymphocyte-specific interferon regulatory factor)
MUM1 (multiple myeloma oncogene 1)
HGNC (Hugo) IRF4
LocusID (NCBI) 3662
Location 6p25.3
Location_base_pair Starts at 391739 and ends at 411443 bp from pter ( according to hg19-Feb_2009)  [Mapping]
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.

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.
Transcription 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.

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.
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.
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 DNA-binding domain.

Mutations

Note Mutations in the distal and proximal sites of the GC-rich sequence of the IRF4 promoter cause a reduction of 62 and 81%, activity in the IRF4 promoter, respectively.

Implicated in

Entity 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. 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.
  
Entity B-cell chronic lymphocytic leukemia (B-CLL)
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.
  
Entity Adult T-cell leukemia (ATL)
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.
  
Entity Primary effusion lymphoma (PEL)
Disease PEL is a clinico-pathological category of B-cell non-Hodgkin'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 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.
  

External links

Nomenclature
HGNC (Hugo)IRF4   6119
Cards
AtlasIRF4ID231ch6p25
Entrez_Gene (NCBI)IRF4  3662  interferon regulatory factor 4
GeneCards (Weizmann)IRF4
Ensembl (Hinxton)ENSG00000137265 [Gene_View]  chr6:391739-411443 [Contig_View]  IRF4 [Vega]
AceView (NCBI)IRF4
Genatlas (Paris)IRF4
WikiGenes3662
SOURCE (Princeton)NM_001195286 NM_002460
Genomic and cartography
GoldenPath (UCSC)IRF4  -  6p25.3   chr6:391739-411443 +  6p25-p23   [Description]    (hg19-Feb_2009)
EnsemblIRF4 - 6p25-p23 [CytoView]
Mapping of homologs : NCBIIRF4 [Mapview]
OMIM254500   601900   
Gene and transcription
Genbank (Entrez)AK130762 AK310149 AW197089 BC015752 BG230623
RefSeq transcript (Entrez)NM_001195286 NM_002460
RefSeq genomic (Entrez)AC_000138 NC_000006 NC_018917 NG_027728 NT_007592 NW_001838972 NW_004929326
Consensus coding sequences : CCDS (NCBI)IRF4
Cluster EST : UnigeneHs.401013 [ NCBI ]
CGAP (NCI)Hs.401013
Alternative Splicing : Fast-db (Paris)GSHG0025358
Alternative Splicing GalleryENSG00000137265
Gene ExpressionIRF4 [ NCBI-GEO ]     IRF4 [ SEEK ]   IRF4 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ15306 (Uniprot)
NextProtQ15306  [Medical]
With graphics : InterProQ15306
Splice isoforms : SwissVarQ15306 (Swissvar)
Domaine pattern : Prosite (Expaxy)IRF_1 (PS00601)    IRF_2 (PS51507)   
Domains : Interpro (EBI)Interferon_reg_fac_CS    Interferon_reg_fact_DNA-bd_dom    Interferon_reg_factor-3    SMAD_dom-like    SMAD_FHA_domain    WHTH_DNA-bd_dom   
Related proteins : CluSTrQ15306
Domain families : Pfam (Sanger)IRF (PF00605)    IRF-3 (PF10401)   
Domain families : Pfam (NCBI)pfam00605    pfam10401   
Domain families : Smart (EMBL)IRF (SM00348)  
DMDM Disease mutations3662
Blocks (Seattle)Q15306
PDB (SRS)2DLL   
PDB (PDBSum)2DLL   
PDB (IMB)2DLL   
PDB (RSDB)2DLL   
Human Protein AtlasENSG00000137265
Peptide AtlasQ15306
HPRD03543
IPIIPI00289982   IPI00215970   IPI00981040   
Protein Interaction databases
DIP (DOE-UCLA)Q15306
IntAct (EBI)Q15306
FunCoupENSG00000137265
BioGRIDIRF4
InParanoidQ15306
Interologous Interaction database Q15306
IntegromeDBIRF4
STRING (EMBL)IRF4
Ontologies - Pathways
Ontology : AmiGOnuclear nucleosome  regulatory region DNA binding  sequence-specific DNA binding transcription factor activity  sequence-specific DNA binding transcription factor activity  protein binding  nucleus  nucleus  nucleolus  cytoplasm  cytosol  transcription, DNA-templated  transcription factor binding  protein-lysine N-methyltransferase activity  cytokine-mediated signaling pathway  negative regulation of toll-like receptor signaling pathway  T cell activation  defense response to protozoan  myeloid dendritic cell differentiation  positive regulation of DNA binding  sequence-specific DNA binding  histone H3 acetylation  histone H4 acetylation  positive regulation of interleukin-10 biosynthetic process  positive regulation of interleukin-2 biosynthetic process  positive regulation of interleukin-13 biosynthetic process  positive regulation of interleukin-4 biosynthetic process  regulation of T-helper cell differentiation  positive regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  interferon-gamma-mediated signaling pathway  type I interferon signaling pathway  T-helper 17 cell lineage commitment  
Ontology : EGO-EBInuclear nucleosome  regulatory region DNA binding  sequence-specific DNA binding transcription factor activity  sequence-specific DNA binding transcription factor activity  protein binding  nucleus  nucleus  nucleolus  cytoplasm  cytosol  transcription, DNA-templated  transcription factor binding  protein-lysine N-methyltransferase activity  cytokine-mediated signaling pathway  negative regulation of toll-like receptor signaling pathway  T cell activation  defense response to protozoan  myeloid dendritic cell differentiation  positive regulation of DNA binding  sequence-specific DNA binding  histone H3 acetylation  histone H4 acetylation  positive regulation of interleukin-10 biosynthetic process  positive regulation of interleukin-2 biosynthetic process  positive regulation of interleukin-13 biosynthetic process  positive regulation of interleukin-4 biosynthetic process  regulation of T-helper cell differentiation  positive regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  interferon-gamma-mediated signaling pathway  type I interferon signaling pathway  T-helper 17 cell lineage commitment  
Pathways : BIOCARTAThe information-processing pathway at the IFN-beta enhancer [Genes]   
REACTOMEIRF4
Protein Interaction DatabaseIRF4
Wikipedia pathwaysIRF4
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)IRF4
SNP (GeneSNP Utah)IRF4
SNP : HGBaseIRF4
Genetic variants : HAPMAPIRF4
1000_GenomesIRF4 
ICGC programENSG00000137265 
Cancer Gene: CensusIRF4 
Somatic Mutations in Cancer : COSMICIRF4 
CONAN: Copy Number AnalysisIRF4 
Mutations and Diseases : HGMDIRF4
OMIM254500    601900   
GENETestsIRF4
Disease Genetic AssociationIRF4
Huge Navigator IRF4 [HugePedia]  IRF4 [HugeCancerGEM]
Genomic VariantsIRF4  IRF4 [DGVbeta]
Exome VariantIRF4
dbVarIRF4
ClinVarIRF4
snp3D : Map Gene to Disease3662
General knowledge
Homologs : HomoloGeneIRF4
Homology/Alignments : Family Browser (UCSC)IRF4
Phylogenetic Trees/Animal Genes : TreeFamIRF4
Chemical/Protein Interactions : CTD3662
Chemical/Pharm GKB GenePA29918
Clinical trialIRF4
Cancer Resource (Charite)ENSG00000137265
Other databases
Probes
Litterature
PubMed106 Pubmed reference(s) in Entrez
CoreMineIRF4
iHOPIRF4

Bibliography

Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25.
Grossman A, Mittrucker HW, Nicholl J, Suzuki A, Chung S, Antonio L, Suggs S, Sutherland GR, Siderovski DP, Mak TW.
Genomics. 1996 Oct 15;37(2):229-33.
PMID 8921401
 
Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma.
Iida S, Rao PH, Butler M, Corradini P, Boccadoro M, Klein B, Chaganti RS, Dalla-Favera R.
Nat Genet. 1997 Oct;17(2):226-30.
PMID 9326949
 
Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function.
Mittrucker HW, Matsuyama T, Grossman A, Kundig TM, Potter J, Shahinian A, Wakeham A, Patterson B, Ohashi PS, Mak TW.
Science. 1997 Jan 24;275(5299):540-3.
PMID 8999800
 
MUM1/IRF4 expression as a frequent event in mature lymphoid malignancies.
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.
Leukemia. 2000 Mar;14(3):449-56.
PMID 10720141
 
Expression of MUM1/IRF4 correlates with clinical outcome in patients with B-cell chronic lymphocytic leukemia.
Chang CC, Lorek J, Sabath DE, Li Y, Chitambar CR, Logan B, Kampalath B, Cleveland RP.
Blood. 2002 Dec 15;100(13):4671-5. Epub 2002 Aug 1.
PMID 12393648
 
Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry.
Falini B, Mason DY.
Blood. 2002 Jan 15;99(2):409-26. Review
PMID 11781220
 
MUM1/IRF4 expression is an unfavorable prognostic factor in B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Ito M, Iida S, Inagaki H, Tsuboi K, Komatsu H, Yamaguchi M, Nakamura N, Suzuki R, Seto M, Nakamura S, Morishima Y, Ueda R.
Jpn J Cancer Res. 2002 Jun;93(6):685-94.
PMID 12079517
 
Repression of IRF-4 target genes in human T cell leukemia virus-1 infection.
Mamane Y, Grandvaux N, Hernandez E, Sharma S, Innocente SA, Lee JM, Azimi N, Lin R, Hiscott J.
Oncogene. 2002 Oct 3;21(44):6751-65.
PMID 12360402
 
Identification of a novel GC-rich binding protein that binds to an indispensable element for constitutive IRF-4 promoter activity in B cells.
Nishiya N, Yamamoto K, Imaizumi Y, Kohno T, Matsuyama T.
Mol Immunol. 2004 Jul;41(9):855-61.
PMID 15261457
 
Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS.
Honma K, Udono H, Kohno T, Yamamoto K, Ogawa A, Takemori T, Kumatori A, Suzuki S, Matsuyama T, Yui K.
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16001-6. Epub 2005 Oct 21.
PMID 16243976
 
Negative regulation of Toll-like-receptor signaling by IRF-4.
Negishi H, Ohba Y, Yanai H, Takaoka A, Honma K, Yui K, Matsuyama T, Taniguchi T, Honda K.
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15989-94. Epub 2005 Oct 19.
PMID 16236719
 
Down-regulation of interferon regulatory factor 4 gene expression in leukemic cells due to hypermethylation of CpG motifs in the promoter region.
Ortmann CA, Burchert A, Holzle K, Nitsche A, Wittig B, Neubauer A, Schmidt M.
Nucleic Acids Res. 2005 Dec 7;33(21):6895-905. Print 2005.
PMID 16396836
 
IRF4 addiction in multiple myeloma.
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.
Nature. 2008 Jul 10;454(7201):226-31. Epub 2008 Jun 22.
PMID 18568025
 
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Contributor(s)

Written01-2009Silvia 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

Citation

This paper should be referenced as such :
Rasi S, Gaidano G . IRF4 (interferon regulatory factor 4). Atlas Genet Cytogenet Oncol Haematol. January 2009 .
URL : http://AtlasGeneticsOncology.org/Genes/IRF4ID231ch6p25.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44637/1/01-2009-IRF4ID231ch6p25.pdf   [ Bibliographic record ]

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indexed on : Fri Apr 18 17:33:20 CEST 2014

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