IRF4 (interferon regulatory factor 4)

2014-02-01 Vipul Shukla , Runqing Lu Affiliation

Identity

HGNC

IRF4

LOCATION

6p25.3

LOCUSID

3662

ALIAS

LSIRF,MUM1,NF-EM5,SHEP8

FUSION GENES

Show Gene Fusions

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.

Proteins

Description

Protein length: 451 amino acids.
Calculated molecular weight of 51,8 kDa.

Expression

IRF4 protein is expressed predominantly in blood cells. However, its expression can also be detected in adipocytes and melanocytes. In blood cells, expression of IRF4 can be detected in T, B, DC and macrophages. Expression of IRF4 in T and B cells is strongly induced by antigen receptor signaling.

Localisation

Nucleus.

Function

In the immune system, IRF4 is critical for development and maturation of multiple lineages of blood cells. In T cells development, IRF4 is essential for the differentiation of Th1, Th2, Th9, Th17 and T reg subsets. In B lymphocytes, IRF4 promotes light chain rearrangement and transcription and is critical for B cell development at the pre-B stage. IRF4 antagonizes Notch signaling and limits the size of marginal zone B cells (Simonetti et al., 2013). In addition, IRF4 is essential for class-switching and plasma cell differentiation. In B cells, IRF4 interacts with Ets family of trancription factor (PU.1/spi-B) through EICE site whereas in T cells, IRF4 interacts with AP-1 family of trancription factor (BATF) through AICE site. Also, IRF4 is required for the differentiation of dendritic cells (DCs), particularly the CD11b(+) subset (Schlitzer et al., 2013). In macrophages, IRF4 promotes the differentiation and polarisation to the M2 subtype also known as the tumor associated macrophages.
Recent studies have identified a role of IRF4 in adipocyte biology. IRF4 has been shown to regulate enzymes required for lipolysis in adipocytes. Therefore, an adipocyte specific deletion of IRF4 causes enhanced lipid synthesis, dysregulated lipid homeostasis eventually leading to obesity.
Interestingly, in melanocytes IRF4 was recently identified to cooperate with another transcription factor, MITF to positively regulate the expression of tyrosinase gene required for melanin synthesis. Additionally, the SNPs in the IRF4 gene locus have been identified as risk alleles for developing melanoma.

Homology

Among IRF family members, IRF4 is highly homologous to IRF8.

Mutations

Germinal

SNPs in the IRF4 gene locus have been identified in patients with chronic lymphocytic leukemia and melanoma.

Somatic

Somatic mutations in DNA binding domain of IRF4 have been identified in a small subset (1,5%) of chronic lymphocytic leukemia (CLL) patients.

Implicated in

Entity name

Multiple myeloma (MM)

Disease

Multiple myeloma (MM) is a plasma cell derived malignancy with a particularly aggressive clinical course. IRF4 is obligatory required for the terminal differetiation of mature B cells to plasma cells and has been shown to play a central role in the pathogenesis of MM. IRF4 is recurrently translocated and juxtaposed to the IgH promoter t(6;14)(p25;q32) in a significant proportion (~21%) of MM cases. More commonly, IRF4 have been shown to be overexpressed without genetic alterations in majority of MM cases and MM cells are particularly sensitive to the down-regulation of IRF4.

Cytogenetics

t(6;14)(p25;q32) --> IRF4 - IgH.

Hybrid gene

The translocation juxtaposes the IgH locus to the IRF4 gene.

Oncogenesis

The precise mechanism for pathogenesis of MM in presence of high levels of IRF4 is mediated by an autoregulatory loop established between IRF4 and c-myc in MM cells. Recently, IRF4 has been shown to regulate caspase-10 leading to disruption of normal autophagy mechanisms in MM cells thereby, causing prolonged survival of these cells.

Entity name

Chronic lymphocytic leukemia (CLL)

Disease

CLL is the most common adult leukemia in the western countries. It is a heterogeneous B-cell malignancy marked by progressive accumulation of CD5 positive mature B lymphocytes. A Genome Wide Association Study (GWAS) recently identified SNPs in the 3 UTR of IRF4 gene locus in patients with CLL. The individuals carrying the risk alleles harboring the SNPs have lower levels of IRF4 and poorer outcomes compared to individuals carrying the non-risk allele. Another study identified mutations in the DNA binding domain of IRF4 in a small subset (1,5%) of CLL cases. More recently, using two distinct murine genetic models, it has been shown that low levels of IRF4 are causally related to the development of CLL.

Prognosis

CLL patients with low levels of IRF4 have aggressive disease course and poor prognosis.

Cytogenetics

Although reciprocal translocations are extremely rare in CLL, a translocation disrupting IRF4 gene locus t(1;6)(p35.3;p25.2) was identified in a small subset of CLL patients with aggressive disease.

Hybrid gene

Mutations in the DNA binding domain of IRF4 with a yet undefined function in B cells were identified in a small subset of CLL cases.

Oncogenesis

The precise mechanism for oncogenesis of CLL in presence of low levels of IRF4 is not yet known.

Entity name

Diffused large B cell lymphoma (DLBCL)

Disease

Diffuse large B cell lymphoma represents a heterogeneous malignancy that arises spontaneously or develop from pre-existing leukemia. On the basis of gene expression profiling DLBCL is divided into three distinct subtypes namely the germinal center subtype (GCB), the activated B cell subtype (ABC) and the mediastinal subtype. The three subtypes presumably arise from three distinct B cell subtypes. IRF4 is primarily overexpressed in the ABC type of DLBCL while GCB subtype is marked by lower expression of IRF4.

Prognosis

IRF4 is overexpressed in the ABC type DLBCL which is most aggressive form of DLBCL and have poorer patient outcomes compared to other subtypes.

Cytogenetics

IRF4 is overexpressed in a small group of patients with a reciprocal translocation between IgG locus and the IRF4 t(1;6)(p35.3;p25.2). The patients carrying the translocation primarily belong to GCB or follicular lymphoma grade 3 type is associated with favorable patient outcomes.

Oncogenesis

IRF4 induces the expression of transcription factor Blimp-1 and directly suppresses the expression of Bcl-6 to allow terminal differentiation of activated B cells to plasma cells. However, this molecular network is short circuited in ABC DLBCL by recurrent mutational inactivation of Blimp-1. Additionally, mutations located in the promoter region of Bcl-6 that disrupt the IRF4 binding sites and leads to enhanced expression of Bcl-6 were identified in a small group of patients. These genetic events disrupt the molecular network required for plasma cell differentiation. However, the precise functional role of IRF4 in pathogenesis of ABC type DLBCL is not well defined.

Entity name

Hodgkins lymphoma (HL)

Disease

Hodgkins lymphoma (HL) is an enigmatic B cell malignancy that is characterized by lack of expression of several B cell markers. The Hodgkin and Reed Sternberg (HRS) cells present in HL cases are presumably derived from germinal center B cells. IRF4 is overexpressed in majority of classical HL cases and is shown to mediate the survival of these cells. Paradoxically, the SNPs in IRF4 linked to its lower expression levels and associated with the development of CLL are also shown to be linked to the risk of developing HL.

Oncogenesis

Whether the overexpression of IRF4 in HRS cells of HL is causal is unclear. However, some studies have linked the survival and proliferation of HRS cells to the expression of IRF4.

Entity name

Primary cutaneous anaplastic large cell lymphoma (C-ALCL)

Disease

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a T cell lymphoma with an indolent disease course and presence of tumor lesions in the skin. The lesions in C-ALCL almost never spread extra-cutaneously and often regress spontaneously. IRF4 is overexpressed in C-ALCL but not in the more aggressive form of the disease known as peripheral T cell lymphoma not otherwise specified (PTCL-NOS). The overexpression of IRF4 in some cases is associated with a recurrent translocations a subset of them placing the IRF4 gene next to the T cell receptor alpha (TCRA) promoter t(6;14)(p25;q11.2). Other translocations identified do not involve TCRA.

Cytogenetics

IRF4 is translocated primarily in the C-ALCL however the precise breakpoints are not defined. In a small subset of the cases with translocations IRF4 is juxtaposed to the TCRA locus t(6;14)(p25;q11.2).

Entity name

B cell acute lymphoblastic leukemia (B-ALL)

Disease

B cell acute lymphoblastic leukemia (B-ALL) is a B cell malignancy derived from early B cells. IRF4 is shown to play a tumor suppressive role in B-ALL. IRF4 is shown to suppress the oncogenesis of both BCR-ABL and c-myc induced B-ALL.

Oncogenesis

IRF4 inhibits B-ALL by regulating the expression of negative regulators of cell cycle p27.

Entity name

Chronic myeloid leukemia (CML)

Disease

Chronic myeloid leukemia (CML) is a myeloproliferative disorder marked by clonal expansion of granulocytes. It is associated with a hallmark translocation and presence of a fusion BCR-ABL protein in majority of patients. IRF4 is shown to be underexpressed in CML patients along with its highly homologous family member IRF8. However the functional role of IRF4 in CML is not well characterized.

Entity name

Virus implicated malignancies

Disease

Viruses like Epstein Barr virus (EBV), human T cell leukemia virus-1 (HTLV1) and Kaposi Sarcoma associated herpes virus (KSHV/HHV-8) are implicated in B cell malignancies, adult T cell leukemia (ATL) and primary effusion lymphoma (PEL) respectively. The proteins encoded by these viruses, directly or indirectly activate NF-kB signaling which in turn activates the expression of IRF4. As a result IRF4 is overexpressed in these virus implicated malignancies. The knockdown of IRF4 in EBV transformed B cells lead to down-regulation of genes involved in cellular proliferation. The role of IRF4 in HTLV-1 induced ATL is not clear however few reports indicate its involvement in regulation of cell cycle associated genes. The role of IRF4 in KSHV induced kaposis sarcoma and PEL is ambiguous. KSHV encodes viral homologs of cellular IRFs called vIRFs. The vIRF4 is shown to inhibit the function of cellular IRF4 leading to induction of lytic cycle for KSHV replication.

Oncogenesis

The role of IRF4 in these viral implicated malignancies is still unclear. However, the activation status of NF-kB by these viruses invariably co-relates with IRF4 expression in these cells.

Entity name

Skin cancer

Disease

Skin cancer is associated with malignant or non-malignant lesions on the skin. Based on the cell of origin, skin cancer can be divided into three types: basal cell carcinoma, squamous cell carcinoma and melanoma. The differential skin pigmentation induced by melanin production alters the risk for skin cancer. Particularly individuals with light skin tones and hence low melanin secretion are more predisposed to developing skin cancer. Until recently there were no known reports for a role of IRF4 in melanocytes. However recently, SNPs identified in the IRF4 gene locus have been shown to be associated with skin pigmentation and the risk for developing skin cancer. The SNP identified in the screen map to a putative enhancer region in the IRF4 gene locus.

Oncogenesis

Recently, the SNP identified in IRF4 locus were demonstrated to decrease IRF4 expression by disruption of specific transcription factor binding sites. Additionally, IRF4 corroborates with micropthalmia associated transcription factor (MITF) to regulate the expression of enzyme tyrosinase responsible for melanin production. These studies point towards a critical role for IRF4 in melanocyte biology and also its association with skin cancer.

Bibliography

Pubmed ID	Last Year	Title	Authors
18713947	2008	IRF-4 functions as a tumor suppressor in early B-cell development.	Acquaviva J et al
12393648	2002	Expression of MUM1/IRF4 correlates with clinical outcome in patients with B-cell chronic lymphocytic leukemia.	Chang CC et al
18758461	2008	A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia.	Di Bernardo MC et al
21356515	2011	Transcriptional control of adipose lipid handling by IRF4.	Eguchi J et al
11781220	2002	Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry.	Falini B et al
18987657	2009	Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas.	Feldman AL et al
22983707	2012	A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes.	Glasmacher E et al
8921401	1996	Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25.	Grossman A et al
16243976	2005	Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS.	Honma K et al
9326949	1997	Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma.	Iida S et al
12079517	2002	MUM1/IRF4 expression is an unfavorable prognostic factor in B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).	Ito M et al
18775669	2008	Interferon regulatory factor 4 and 8 in B-cell development.	Lu R et al
12360402	2002	Repression of IRF-4 target genes in human T cell leukemia virus-1 infection.	Mamane Y et al
8999800	1997	Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function.	Mittrücker HW et al
16236719	2005	Negative regulation of Toll-like-receptor signaling by IRF-4.	Negishi H et al
15261457	2004	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 et al
16396836	2005	Down-regulation of interferon regulatory factor 4 gene expression in leukemic cells due to hypermethylation of CpG motifs in the promoter region.	Ortmann CA et al
24267888	2013	A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway.	Praetorius C et al
20729857	2010	The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection.	Satoh T et al
23706669	2013	IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses.	Schlitzer A et al
19383829	2009	IRF4: Immunity. Malignancy! Therapy?	Shaffer AL et al
23926303	2013	A role for IRF4 in the development of CLL.	Shukla V et al
24323359	2013	IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity.	Simonetti G et al
10720141	2000	MUM1/IRF4 expression as a frequent event in mature lymphoid malignancies.	Tsuboi K et al
22698399	2012	Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma.	Yang Y et al
19182775	2009	Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses.	Zheng Y et al

Other Information

Locus ID:

NCBI: 3662
MIM: 601900
HGNC: 6119
Ensembl: ENSG00000137265

Variants:

dbSNP: 3662
ClinVar: 3662
TCGA: ENSG00000137265
COSMIC: IRF4

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000137265	ENST00000380956	Q15306
ENSG00000137265	ENST00000493114	F2Z3D5

Expression (GTEx)

100

150

200

250

300

350

400

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Immune System	REACTOME	R-HSA-168256
Cytokine Signaling in Immune system	REACTOME	R-HSA-1280215
Interferon Signaling	REACTOME	R-HSA-913531
Interferon alpha/beta signaling	REACTOME	R-HSA-909733
Interferon gamma signaling	REACTOME	R-HSA-877300
Signaling by Interleukins	REACTOME	R-HSA-449147
Th17 cell differentiation	KEGG	ko04659
Th17 cell differentiation	KEGG	hsa04659
Interleukin-4 and 13 signaling	REACTOME	R-HSA-6785807

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
22025054	2011	Transcriptional regulation of macrophage polarization: enabling diversity with identity.	607
20674401	2010	Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells.	180
18483556	2008	A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation.	168
18483556	2008	A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation.	168
20585627	2010	Web-based, participant-driven studies yield novel genetic associations for common traits.	155
18758461	2008	A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia.	143
22698399	2012	Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma.	138
19047678	2009	Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas.	105
24995979	2014	IRF4 is a key thermogenic transcriptional partner of PGC-1α.	87
19710684	2010	Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma.	66

Citation

Vipul Shukla ; Runqing Lu

IRF4 (interferon regulatory factor 4)

Atlas Genet Cytogenet Oncol Haematol. 2014-02-01

Online version: http://atlasgeneticsoncology.org/gene/231/irf4

Historical Card

2009-01-01 IRF4 (interferon regulatory factor 4) by Silvia Rasi,Gianluca Gaidano Affiliation

Division of Hematology, Department of Clinical, Experimental Medicine & Center of Biotechnologies for Applied Medical Research, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy