Download Gene Section IRF4 (interferon regulatory factor 4) Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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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
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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
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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.
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