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Gene Section
Review
IRF4 (interferon regulatory factor 4)
Vipul Shukla, Runqing Lu
Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha,
NE 68118, USA (VS, RL)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/IRF4ID231ch6p25.html
DOI: 10.4267/2042/54034
This article is an update of :
Rasi S, Gaidano G. IRF4 (interferon regulatory factor 4). Atlas Genet Cytogenet Oncol Haematol 2009;13(12):941-943.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
mRNA is expressed at high levels in lymphoid
tissues, in skin and in tonsils.
Review on IRF4, with data on DNA/RNA, on the
protein encoded and where the gene is implicated.
Protein
Identity
Description
Protein length: 451 amino acids.
Calculated molecular weight of 51,8 kDa.
Other names: IRF-4, LSIRF, MUM1, NF-EM5
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 transcription factors and is a
critical transcriptional regulator of immune system
development and function.
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).
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.
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IRF4 (interferon regulatory factor 4)
Shukla V, Lu R
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.
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/Mutated 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.
Homology
Chronic lymphocytic leukemia (CLL)
Among IRF family members, IRF4 is highly
homologous to IRF8.
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.
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
Multiple myeloma (MM)
Disease
Multiple myeloma (MM) is a plasma cell derived
malignancy with a particularly aggressive clinical
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IRF4 (interferon regulatory factor 4)
Shukla V, Lu R
Hodgkins lymphoma (HL)
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/Mutated 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.
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.
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.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
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).
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 BALL. 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.
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IRF4 (interferon regulatory factor 4)
Shukla V, Lu R
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.
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.
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 downregulation 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 kaposi's
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.
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Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
This article should be referenced as such:
Shukla V, Lu R. IRF4 (interferon regulatory factor 4). Atlas
Genet Cytogenet Oncol Haematol. 2014; 18(9):663-667.
667