Disease relevance of IRF4

• Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma [1].
• Previous work has demonstrated that the B-cell proliferation/differentiation marker MUM1/IRF4 is detected in malignant melanoma and hematolymphoid malignancies, but not in any other neoplasm tested (including colonic, lung, breast, and ovarian carcinomas) [2].
• Expression of MUM1/IRF4 selectively clusters with primary effusion lymphoma among lymphomatous effusions: implications for disease histogenesis and pathogenesis [3].
• Here, we show that IRF4 is constitutively expressed in adult T-cell leukemia (ATL)-derived cell lines, which were infected with human T-cell leukemia virus type-I, but hardly expressed the trans-activator protein, Tax [4].
• We wanted to study the expression of interferon regulatory factor 4 (IRF4) in various hematologic disorders, especially chronic myeloid leukemia (CML), and its association with response to interferon alfa (IFN-alpha) treatment in CML [5].

High impact information on IRF4

• Finally, IRF4 and IRF8 together control the termination of pre-B cell receptor signaling and thus promote differentiation to small pre-B cells undergoing light-chain gene rearrangements [6].
• PU.1 recruits the binding of a second B cell-restricted nuclear factor, NF-EM5, to a DNA site in the immunoglobulin kappa 3' enhancer [7].
• Effect of PU.1 phosphorylation on interaction with NF-EM5 and transcriptional activation [7].
• Expression of wild-type PU.1 increased expression of a reporter construct containing the PU.1 and NF-EM5 binding sites nearly sixfold, whereas the Ser148 mutant form only weakly activated transcription [7].
• Phosphorylation of bacterially produced PU.1 by purified casein kinase II modified it to a form that interacted with NF-EM5 and that recruited NF-EM5 to bind to DNA [7].

Biological context of IRF4

• IRF4 expression was then correlated with cytogenetic response to IFN-alpha [5].
• Computer analysis of the human IRF4 promoter revealed several putative STAT and NF-kappaB binding sites, as well as an IRF/Ets binding site [8].
• Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-gamma (MIG) gene expression in B-cell malignancy [9].
• Taken together, our results indicate that IRF4 is involved in the pathogenesis of ATL through its positive effect on the cell cycle, and that IRF4 can be used as a molecular marker of clinical subtype in ATL [4].
• In addition, ectopic expression of IRF4 in Rat-1 fibroblasts increased the S and G2 / M phase population significantly [4].

Anatomical context of IRF4

• We present evidence that primary murine and human macrophages express IRF4, thereby extending its range of expression to myeloid cells [10].
• ICSBP expression is restricted to lymphoid and myeloid cells, whereas IRF4 expression has been reported to be lymphoid-restricted [10].
• Since expression of IRF-4 is mostly confined to lymphoid cells, these data provide a potential mechanism by which IL-4-inducible genes can be regulated in a lineage-specific manner [11].
• We have isolated a novel cDNA clone encoding interferon (IFN) consensus sequence-binding protein in adult T-cell leukemia cell line or activated T cells (ICSAT); this protein is the human homolog of the recently cloned Pip/LSIRF [12].
• Surprisingly hLSIRF mRNA was also found in the melanoma line G361 and is expressed in normal melanocytes as well [13].

Associations of IRF4 with chemical compounds

• IRF-4 is transiently expressed in anti-CD3 and PMA/ionomycin-stimulated T lymphocytes but not in continuous non-Tax-expressing T cell lines [14].
• IRF-4 expression in the human myeloid lineage: up-regulation during dendritic cell differentiation and inhibition by 1alpha,25-dihydroxyvitamin D3 [15].
• Second, using a restriction-PCR-assay and bisulfite-sequencing we identified specifically methylated CpG sites in IRF-4-negative but not in IRF-4-positive cells [16].

Physical interactions of IRF4

• In this set of studies, we demonstrate that IRF-4 interacts with B lymphocyte-induced maturation protein/positive regulatory domain I-binding factor 1 (Blimp1/PRD1-BF1), a Krüppel-type zinc finger protein whose expression correlates with terminal B cell differentiation [17].
• The purified IRF-4 was also shown to be capable of binding DNA in a PU.1-dependent manner by electrophoretic mobility shift analysis [18].
• A series of deletion mutants of IRF-4 revealed that its DNA-binding domain was necessary and sufficient to antagonize the IRF-1-dependent transactivation [19].

Regulatory relationships of IRF4

• The transactivating ability of IRF-4 is blocked by the repressor factor BCL-6 [11].
• Higher concentration of IRF-4 induced Prdm1 and consequently the transition from a germinal center gene expression program to that of a plasma cell [20].
• Interestingly, the IRF-1-dependent transactivation is inhibited in the presence of IRF-4, but not IRF-2 [19].

Other interactions of IRF4

• Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4 [11].
• A novel interferon regulatory factor family transcription factor, ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated genes [12].
• More than half of the cases displayed bcl-6 gene mutations, which usually occurred together with functioning somatic IgV(H) gene mutations, and BCL-6 and/or MUM1/IRF4 expression [21].
• However, several partner chromosomes have not been detected by conventional cytogenetic methods; for example, 4p16.3 (FGFR3), 6p25.3 (IRF4), and 16q23 (c-maf) [22].
• The other partners were 19q13 (BCL3), 6p25 (MUM1/IRF4), 1q36, and chromosome 8 identified in one patient each [23].

Analytical, diagnostic and therapeutic context of IRF4

• Second, MUM1/IRF4 may help in the differential diagnosis of PEL among other lymphomas involving the serous body cavities [3].
• Furthermore, we find that IRF-4 can interact with signal transducer and activator of transcription (Stat)6 and drive the expression of IL-4-inducible genes [11].
• In Northern blot analysis, a single transcript of approximately 5 kb was highly expressed in spleen and peripheral blood lymphocyte. hLSIRF mRNA was rapidly induced in peripheral T cells after crosslinking the T-cell receptor [13].
• To elucidate its role in B-cell malignancies, we prepared MUM1-expressing Ba/F3 cells, which proliferated until higher cellular density than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1 [9].
• Following purification through immobilized metal affinity, hydrophobic interaction, and gel permeation chromatographies, the renatured protein was shown to be structurally and physically equivalent to a sample of IRF-4 produced in the soluble fraction of E. coli cells [18].

References