Please wait a minute...
Shopping Cart Email List Chinese
Advanced Search Fig/Tab
Frontiers in Biology

ISSN 1674-7984

ISSN 1674-7992(Online)

CN 11-5892/Q

Featured Articles  |  Most Downloaded  |  Most Reading
Online Submission Subscribe to Our RSS Content Feed
Front. Biol.    2014, Vol. 9 Issue (4) : 269-282    https://doi.org/10.1007/s11515-014-1318-y
REVIEW
IRF4 and IRF8: governing the virtues of B lymphocytes
Vipul SHUKLA(),Runqing LU()
Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
 Download: PDF(579 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract

Interferon regulatory factor 4 (IRF4) and IRF8 are critical regulators of immune system development and function. In B lymphocytes, IRF4 and IRF8 have been shown to control important events during their development and maturation including pre-B cell differentiation, induction of B cell tolerance pathways, marginal zone B cell development, germinal center reaction and plasma cell differentiation. Mechanistically, IRF4 and IRF8 are found to function redundantly to control certain stages of B cell development, but in other stages, they function nonredundantly to play distinct roles in B cell biology. In line with their essential roles in B cell development, deregulated expressions of IRF4 and IRF8 have been associated to the pathogenesis of several B cell malignancies and diseases. Recent studies have elucidated diverse transcriptional networks regulated by IRF4 and IRF8 at distinct B cell developmental stages and related malignancies. In this review we will discuss the recent advances for the roles of IRF4 and IRF8 during B cell development and associated diseases.
Keywords IRF4      IRF8      B lymphocytes      transcriptional regulation      leukemia and lymphoma      B cell development     
Corresponding Author(s): Vipul SHUKLA   
Issue Date: 11 August 2014
 Cite this article:   
Vipul SHUKLA,Runqing LU. IRF4 and IRF8: governing the virtues of B lymphocytes[J]. Front. Biol., 2014, 9(4): 269-282.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-014-1318-y
https://academic.hep.com.cn/fib/EN/Y2014/V9/I4/269
Fig.1  Regulation of B cell development by IRF4 and IRF8. The stages of B cell development regulated jointly by IRF4 and IRF8 are indicated by black arrows. Other stages of B cell development regulated exclusively by IRF4 or IRF8 are indicated by green or red arrows, respectively.
Fig.2  IRF4 and IRF8 utilize multiple mechanisms to control pre-B cell Development. Pre-BCR signaling leads to expression of IRF4 and IRF8 that directly promotes light chain rearrangement. IRF4 and IRF8 also induce Ikaros and aiolos to inhibit pre-B cell proliferation. Ikaros directly suppresses expression of c-myc, surrogate light chain and integrins. Moreover, IRF4 regulates the expression of CXCR4, which leads to migration of pre-B cells toward CXCL12 expressing stromal cells and away from IL-7 expressing stromal cells. This leads to attenuation of IL-7 signaling.
Fig.3  Role of IRF4 in germinal center (GC) reaction. At low levels, IRF4 (IRF4low) binds cooperatively with Ets and AP-1 family members at EICE/AICE motifs and is critical for induction of Bcl6, Obf1 and AID to initiate GC reaction. In centrocytes located in light zone, high levels of IRF4 (IRF4hi) is induced by antigen binding to high avidity BCRs. High levels of IRF4 cause a shift in binding of IRF4 from EICE/AICE motifs to low affinity ISRE motifs. IRF4 binding to ISRE induces Blimp-1 and represses Bcl6 to end GC reaction and to initiate plasma cell differentiation program.
Fig.4  Role of IRF4 and IRF8 in B cell Malignancies. Green arrows indicate malignancies associated with deregulated IRF4 expression. Red arrows indicate malignancies associated with deregulated expression of IRF8. Black arrows indicate malignancies associated with deregulated expression of both IRF4 and IRF8, however; their roles in these malignancies are not essentially redundant.
1 Acquaviva J, Chen X, Ren R (2008). IRF-4 functions as a tumor suppressor in early B-cell development. Blood, 112(9): 3798–3806
doi: 10.1182/blood-2007-10-117838 pmid: 18713947
2 Affer M, Chesi M, Chen W D, Keats J J, Demchenko Y N, Tamizhmani K, Garbitt V M, Riggs D L, Brents L A, Roschke A V, Van Wier S, Fonseca R, Bergsagel P L, Kuehl W M (2014). Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia, (epub ahead of print)
doi: 10.1038/leu.2014.70 pmid: 24518206
3 Aldinucci D, Celegato M, Borghese C, Colombatti A, Carbone A (2011). IRF4 silencing inhibits Hodgkin lymphoma cell proliferation, survival and CCL5 secretion. Br J Haematol, 152(2): 182–190
doi: 10.1111/j.1365-2141.2010.08497.x pmid: 21114485
4 Aldinucci D, Rapana’ B, Olivo K, Lorenzon D, Gloghini A, Colombatti A, Carbone A (2010). IRF4 is modulated by CD40L and by apoptotic and anti-proliferative signals in Hodgkin lymphoma. Br J Haematol, 148(1): 115–118
doi: 10.1111/j.1365-2141.2009.07945.x pmid: 19821826
5 Alizadeh A A, Eisen M B, Davis R E, Ma C, Lossos I S, Rosenwald A, Boldrick J C, Sabet H, Tran T, Yu X, Powell J I, Yang L, Marti G E, Moore T, Hudson J Jr, Lu L, Lewis D B, Tibshirani R, Sherlock G, Chan W C, Greiner T C, Weisenburger D D, Armitage J O, Warnke R, Levy R, Wilson W, Grever M R, Byrd J C, Botstein D, Brown P O, Staudt L M (2000). Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature, 403(6769): 503–511
doi: 10.1038/35000501 pmid: 10676951
6 Allan J M, Sunter N J, Bailey J R, Pettitt A R, Harris R J, Pepper C, Fegan C, Hall A G, Deignan L, Bacon C M, Pointon J C, Houlston R S, Broderick P, Mainou-Fowler T, Jackson G H, Summerfield G, Evans P A, Strefford J C, Parker A, Oscier D, Pratt G, Allsup D J (2010). Variant IRF4/MUM1 associates with CD38 status and treatment-free survival in chronic lymphocytic leukaemia. Leukemia, 24(4): 877–881
doi: 10.1038/leu.2009.298 pmid: 20090783
7 Arguello M, Sgarbanti M, Hernandez E, Mamane Y, Sharma S, Servant M, Lin R, Hiscott J (2003). Disruption of the B-cell specific transcriptional program in HHV-8 associated primary effusion lymphoma cell lines. Oncogene, 22(7): 964–973
doi: 10.1038/sj.onc.1206270 pmid: 12592383
8 Banerjee S, Lu J, Cai Q, Saha A, Jha H C, Dzeng R K, Robertson E S (2013). The EBV Latent Antigen 3C Inhibits Apoptosis through Targeted Regulation of Interferon Regulatory Factors 4 and 8. PLoS Pathog, 9(5): e1003314
doi: 10.1371/journal.ppat.1003314 pmid: 23658517
9 Becker A M, Michael D G, Satpathy A T, Sciammas R, Singh H, Bhattacharya D (2012). IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors. Blood, 119(9): 2003–2012
doi: 10.1182/blood-2011-06-364976 pmid: 22238324
10 Bevington S, Boyes J (2013). Transcription-coupled eviction of histones H2A/H2B governs V(D)J recombination. EMBO J, 32(10): 1381–1392
doi: 10.1038/emboj.2013.42 pmid: 23463099
11 Bollig N, Brüstle A, Kellner K, Ackermann W, Abass E, Raifer H, Camara B, Brendel C, Giel G, Bothur E, Huber M, Paul C, Elli A, Kroczek R A, Nurieva R, Dong C, Jacob R, Mak T W, Lohoff M (2012). Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation. Proc Natl Acad Sci USA, 109(22): 8664–8669
doi: 10.1073/pnas.1205834109 pmid: 22552227
12 Bouamar H, Abbas S, Lin A P, Wang L, Jiang D, Holder K N, Kinney M C, Hunicke-Smith S, Aguiar R C (2013). A capture-sequencing strategy identifies IRF8, EBF1, and APRIL as novel IGH fusion partners in B-cell lymphoma. Blood, 122(5): 726–733
doi: 10.1182/blood-2013-04-495804 pmid: 23775715
13 Brass A L, Kehrli E, Eisenbeis C F, Storb U, Singh H (1996). Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev, 10(18): 2335–2347
doi: 10.1101/gad.10.18.2335 pmid: 8824592
14 Brass A L, Zhu A Q, Singh H (1999). Assembly requirements of PU.1-Pip (IRF-4) activator complexes: inhibiting function in vivo using fused dimers. EMBO J, 18(4): 977–991
doi: 10.1093/emboj/18.4.977 pmid: 10022840
15 Broderick P, Cunningham D, Vijayakrishnan J, Cooke R, Ashworth A, Swerdlow A, Houlston R (2010). IRF4 polymorphism rs872071 and risk of Hodgkin lymphoma. Br J Haematol, 148(3): 413–415
doi: 10.1111/j.1365-2141.2009.07946.x pmid: 19804451
16 Brüstle A, Heink S, Huber M, Rosenpl?nter C, Stadelmann C, Yu P, Arpaia E, Mak T W, Kamradt T, Lohoff M (2007). The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol, 8(9): 958–966
doi: 10.1038/ni1500 pmid: 17676043
17 Busslinger M (2004). Transcriptional control of early B cell development. Annu Rev Immunol, 22(1): 55–79
doi: 10.1146/annurev.immunol.22.012703.104807 pmid: 15032574
18 Cadera E J, Wan F, Amin R H, Nolla H, Lenardo M J, Schlissel M S (2009). NF-kappaB activity marks cells engaged in receptor editing. J Exp Med, 206(8): 1803–1816
doi: 10.1084/jem.20082815 pmid: 19581408
19 Cattoretti G, Shaknovich R, Smith P M, J?ck H M, Murty V V, Alobeid B (2006). Stages of germinal center transit are defined by B cell transcription factor coexpression and relative abundance. J Immunol, 177(10): 6930–6939
doi: 10.4049/jimmunol.177.10.6930 pmid: 17082608
20 Chang C C, Lorek J, Sabath D E, Li Y, Chitambar C R, Logan B, Kampalath B, Cleveland R P (2002). Expression of MUM1/IRF4 correlates with clinical outcome in patients with B-cell chronic lymphocytic leukemia. Blood, 100(13): 4671–4675
doi: 10.1182/blood-2002-01-0104 pmid: 12393648
21 Clark M R, Mandal M, Ochiai K, Singh H (2014). Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling. Nat Rev Immunol, 14(2): 69–80
doi: 10.1038/nri3570 pmid: 24378843
22 Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, Belz G T, Smyth G K, Busslinger M, Nutt S L, Kallies A (2011). The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol, 12(4): 304–311
doi: 10.1038/ni.2006 pmid: 21378976
23 Crowther-Swanepoel D, Broderick P, Ma Y, Robertson L, Pittman A M, Price A, Twiss P, Vijayakrishnan J, Qureshi M, Dyer M J, Matutes E, Dearden C, Catovsky D, Houlston R S (2010). Fine-scale mapping of the 6p25.3 chronic lymphocytic leukaemia susceptibility locus. Hum Mol Genet, 19(9): 1840–1845
doi: 10.1093/hmg/ddq044 pmid: 20123861
24 Decker T, Pasca di Magliano M, McManus S, Sun Q, Bonifer C, Tagoh H, Busslinger M (2009). Stepwise activation of enhancer and promoter regions of the B cell commitment gene Pax5 in early lymphopoiesis. Immunity, 30(4): 508–520
doi: 10.1016/j.immuni.2009.01.012 pmid: 19345119
25 Di Bernardo M C, Crowther-Swanepoel D, Broderick P, Webb E, Sellick G, Wild R, Sullivan K, Vijayakrishnan J, Wang Y, Pittman A M, Sunter N J, Hall A G, Dyer M J, Matutes E, Dearden C, Mainou-Fowler T, Jackson G H, Summerfield G, Harris R J, Pettitt A R, Hillmen P, Allsup D J, Bailey J R, Pratt G, Pepper C, Fegan C, Allan J M, Catovsky D, Houlston R S (2008). A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat Genet, 40(10): 1204–1210
doi: 10.1038/ng.219 pmid: 18758461
26 Eguchi J, Wang X, Yu S, Kershaw E E, Chiu P C, Dushay J, Estall J L, Klein U, Maratos-Flier E, Rosen E D (2011). Transcriptional control of adipose lipid handling by IRF4. Cell Metab, 13(3): 249–259
doi: 10.1016/j.cmet.2011.02.005 pmid: 21356515
27 Escalante C R, Brass A L, Pongubala J M, Shatova E, Shen L, Singh H, Aggarwal A K (2002). Crystal structure of PU.1/IRF-4/DNA ternary complex. Mol Cell, 10(5): 1097–1105
doi: 10.1016/S1097-2765(02)00703-7 pmid: 12453417
28 Feng J, Wang H, Shin D M, Masiuk M, Qi C F, Morse H C3rd (2011). IFN regulatory factor 8 restricts the size of the marginal zone and follicular B cell pools. J Immunol, 186(3): 1458–1466
doi: 10.4049/jimmunol.1001950 pmid: 21178004
29 Forero A, Moore P S, Sarkar S N (2013). Role of IRF4 in IFN-stimulated gene induction and maintenance of Kaposi sarcoma-associated herpesvirus latency in primary effusion lymphoma cells. J Immunol, 191(3): 1476–1485
doi: 10.4049/jimmunol.1202514 pmid: 23804715
30 Gao Y, Nish S A, Jiang R, Hou L, Licona-Limón P, Weinstein J S, Zhao H, Medzhitov R (2013). Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity, 39(4): 722–732
doi: 10.1016/j.immuni.2013.08.028 pmid: 24076050
31 Giese N A, Gabriele L, Doherty T M, Klinman D M, Tadesse-Heath L, Contursi C, Epstein S L, Morse H C3rd (1997). Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression. J Exp Med, 186(9): 1535–1546
doi: 10.1084/jem.186.9.1535 pmid: 9348311
32 Glasmacher E, Agrawal S, Chang A B, Murphy T L, Zeng W, Vander Lugt B, Khan A A, Ciofani M, Spooner C J, Rutz S, Hackney J, Nurieva R, Escalante C R, Ouyang W, Littman D R, Murphy K M, Singh H (2012). A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. Science, 338(6109): 975–980
doi: 10.1126/science.1228309 pmid: 22983707
33 Guo S, Li Z Z, Jiang D S, Lu Y Y, Liu Y, Gao L, Zhang S M, Lei H, Zhu L H, Zhang X D, Liu D P, Li H (2014). IRF4 is a novel mediator for neuronal survival in ischaemic stroke. Cell Death Differ, 21(6): 888–903
doi: 10.1038/cdd.2014.9 pmid: 24510125
34 Hardy R R (2006). B-1 B cell development. J Immunol, 177(5): 2749–2754
doi: 10.4049/jimmunol.177.5.2749 pmid: 16920907
35 Havelange V, Pekarsky Y, Nakamura T, Palamarchuk A, Alder H, Rassenti L, Kipps T, Croce C M (2011). IRF4 mutations in chronic lymphocytic leukemia. Blood, 118(10): 2827–2829
doi: 10.1182/blood-2011-04-350579 pmid: 21791429
36 Heizmann B, Kastner P, Chan S (2013). Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals. J Exp Med, 210(13): 2823–2832
doi: 10.1084/jem.20131735 pmid: 24297995
37 Hodawadekar S, Park K, Farrar M A, Atchison M L (2012). A developmentally controlled competitive STAT5-PU.1 DNA binding mechanism regulates activity of the Ig κ E3′ enhancer. J Immunol, 188(5): 2276–2284
doi: 10.4049/jimmunol.1102239 pmid: 22279106
38 Iida S, Rao P H, Butler M, Corradini P, Boccadoro M, Klein B, Chaganti R S, Dalla-Favera R (1997). Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nat Genet, 17(2): 226–230
doi: 10.1038/ng1097-226 pmid: 9326949
39 Jiang D S, Bian Z Y, Zhang Y, Zhang S M, Liu Y, Zhang R, Chen Y, Yang Q, Zhang X D, Fan G C, Li H (2013). Role of interferon regulatory factor 4 in the regulation of pathological cardiac hypertrophy. Hypertension, 61(6): 1193–1202
doi: 10.1161/HYPERTENSIONAHA.111.00614 pmid: 23589561
40 Jiang D S, Wei X, Zhang X F, Liu Y, Zhang Y, Chen K, Gao L, Zhou H, Zhu X H, Liu P P, Bond Lau W, Ma X, Zou Y, Zhang X D, Fan G C, Li H (2014a). IRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling. Nat Commun, 5: 3303
doi: 10.1038/ncomms4303 pmid: 24526256
41 Jiang S, Willox B, Zhou H, Holthaus A M, Wang A, Shi T T, Maruo S, Kharchenko P V, Johannsen E C, Kieff E, Zhao B (2014b). Epstein-Barr virus nuclear antigen 3C binds to BATF/IRF4 or SPI1/IRF4 composite sites and recruits Sin3A to repress CDKN2A. Proc Natl Acad Sci USA, 111(1): 421–426
doi: 10.1073/pnas.1321704111 pmid: 24344258
42 Johnson K, Hashimshony T, Sawai C M, Pongubala J M, Skok J A, Aifantis I, Singh H (2008). Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling. Immunity, 28(3): 335–345
doi: 10.1016/j.immuni.2007.12.019 pmid: 18280186
43 Joshi I, Yoshida T, Jena N, Qi X, Zhang J, Van Etten R A, Georgopoulos K (2014). Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia. Nat Immunol, 15(3): 294–304
doi: 10.1038/ni.2821 pmid: 24509510
44 Klein U, Casola S, Cattoretti G, Shen Q, Lia M, Mo T, Ludwig T, Rajewsky K, Dalla-Favera R (2006). Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol, 7(7): 773–782
doi: 10.1038/ni1357 pmid: 16767092
45 Konieczna I, Horvath E, Wang H, Lindsey S, Saberwal G, Bei L, Huang W, Platanias L, Eklund E A (2008). Constitutive activation of SHP2 in mice cooperates with ICSBP deficiency to accelerate progression to acute myeloid leukemia. J Clin Invest, 118(3): 853–867
pmid: 18246201
46 Kwon H, Thierry-Mieg D, Thierry-Mieg J, Kim H P, Oh J, Tunyaplin C, Carotta S, Donovan C E, Goldman M L, Tailor P, Ozato K, Levy D E, Nutt S L, Calame K, Leonard W J (2009). Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity, 31(6): 941–952
doi: 10.1016/j.immuni.2009.10.008 pmid: 20064451
47 Lamy L, Ngo V N, Emre N C, Shaffer A L 3rd, Yang Y, Tian E, Nair V, Kruhlak M J, Zingone A, Landgren O, Staudt L M (2013). Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell, 23(4): 435–449
doi: 10.1016/j.ccr.2013.02.017 pmid: 23541952
48 Lee C H, Melchers M, Wang H, Torrey T A, Slota R, Qi C F, Kim J Y, Lugar P, Kong H J, Farrington L, van der Zouwen B, Zhou J X, Lougaris V, Lipsky P E, Grammer A C, Morse H C 3rd (2006). Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J Exp Med, 203(1): 63–72
doi: 10.1084/jem.20051450 pmid: 16380510
49 Lee H R, Do?anay S, Chung B, Toth Z, Brulois K, Lee S, Kanketayeva Z, Feng P, Ha T, Jung J U (2014). Kaposi’s sarcoma-associated herpesvirus viral interferon regulatory factor 4 (vIRF4) targets expression of cellular IRF4 and the Myc gene to facilitate lytic replication. J Virol, 88(4): 2183–2194
doi: 10.1128/JVI.02106-13 pmid: 24335298
50 Lenz G, Nagel I, Siebert R, Roschke A V, Sanger W, Wright G W, Dave S S, Tan B, Zhao H, Rosenwald A, Muller-Hermelink H K, Gascoyne R D, Campo E, Jaffe E S, Smeland E B, Fisher R I, Kuehl W M, Chan W C, Staudt L M (2007). Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. J Exp Med, 204(3): 633–643
doi: 10.1084/jem.20062041 pmid: 17353367
51 Lenz G, Wright G W, Emre N C, Kohlhammer H, Dave S S, Davis R E, Carty S, Lam L T, Shaffer A L, Xiao W, Powell J, Rosenwald A, Ott G, Muller-Hermelink H K, Gascoyne R D, Connors J M, Campo E, Jaffe E S, Delabie J, Smeland E B, Rimsza L M, Fisher R I, Weisenburger D D, Chan W C, Staudt L M (2008). Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci USA, 105(36): 13520–13525
doi: 10.1073/pnas.0804295105 pmid: 18765795
52 Li H, Kaminski M S, Li Y, Yildiz M, Ouillette P, Jones S, Fox H, Jacobi K, Saiya-Cork K, Bixby D, Lebovic D, Roulston D, Shedden K, Sabel M, Marentette L, Cimmino V, Chang A E, Malek S N (2014). Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma. Blood, 123(10): 1487–1498
pmid: 24435047
53 Li P, Spolski R, Liao W, Wang L, Murphy T L, Murphy K M, Leonard W J (2012). BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature, 490(7421): 543–546
doi: 10.1038/nature11530 pmid: 22992523
54 Lohoff M, Mittrücker H W, Prechtl S, Bischof S, Sommer F, Kock S, Ferrick D A, Duncan G S, Gessner A, Mak T W (2002). Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc Natl Acad Sci USA, 99(18): 11808–11812
doi: 10.1073/pnas.182425099 pmid: 12189207
55 Lopez-Girona A, Heintel D, Zhang L H, Mendy D, Gaidarova S, Brady H, Bartlett J B, Schafer P H, Schreder M, Bolomsky A, Hilgarth B, Zojer N, Gisslinger H, Ludwig H, Daniel T, J?ger U, Chopra R (2011). Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response. Br J Haematol, 154(3): 325–336
doi: 10.1111/j.1365-2141.2011.08689.x pmid: 21707574
56 Lu R (2008). Interferon regulatory factor 4 and 8 in B-cell development. Trends Immunol, 29(10): 487–492
doi: 10.1016/j.it.2008.07.006 pmid: 18775669
57 Lu R, Medina K L, Lancki D W, Singh H (2003). IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development. Genes Dev, 17(14): 1703–1708
doi: 10.1101/gad.1104803 pmid: 12832394
58 Ma S, Pathak S, Mandal M, Trinh L, Clark M R, Lu R (2010). Ikaros and Aiolos inhibit pre-B-cell proliferation by directly suppressing c-Myc expression. Mol Cell Biol, 30(17): 4149–4158
doi: 10.1128/MCB.00224-10 pmid: 20566697
59 Ma S, Pathak S, Trinh L, Lu R (2008). Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B-cell receptor and promote cell-cycle withdrawal in pre-B-cell development. Blood, 111(3): 1396–1403
doi: 10.1182/blood-2007-08-110106 pmid: 17971486
60 Ma S, Shukla V, Fang L, Gould K A, Joshi S S, Lu R (2013). Accelerated development of chronic lymphocytic leukemia in New Zealand Black mice expressing a low level of interferon regulatory factor 4. J Biol Chem, 288(37): 26430–26440
doi: 10.1074/jbc.M113.475913 pmid: 23897826
61 Ma S, Turetsky A, Trinh L, Lu R (2006). IFN regulatory factor 4 and 8 promote Ig light chain kappa locus activation in pre-B cell development. J Immunol, 177(11): 7898–7904
doi: 10.4049/jimmunol.177.11.7898 pmid: 17114461
62 Man K, Miasari M, Shi W, Xin A, Henstridge D C, Preston S, Pellegrini M, Belz G T, Smyth G K, Febbraio M A, Nutt S L, Kallies A (2013). The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat Immunol, 14(11): 1155–1165
doi: 10.1038/ni.2710 pmid: 24056747
63 Mandal M, Powers S E, Maienschein-Cline M, Bartom E T, Hamel K M, Kee B L, Dinner A R, Clark M R (2011). Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2. Nat Immunol, 12(12): 1212–1220
doi: 10.1038/ni.2136 pmid: 22037603
64 Mandelbaum J, Bhagat G, Tang H, Mo T, Brahmachary M, Shen Q, Chadburn A, Rajewsky K, Tarakhovsky A, Pasqualucci L, Dalla-Favera R (2010). BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell, 18(6): 568–579
doi: 10.1016/j.ccr.2010.10.030 pmid: 21156281
65 Mittrücker H W, Matsuyama T, Grossman A, Kündig T M, Potter J, Shahinian A, Wakeham A, Patterson B, Ohashi P S, Mak T W (1997). Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science, 275(5299): 540–543
doi: 10.1126/science.275.5299.540 pmid: 8999800
66 Ochiai K, Maienschein-Cline M, Simonetti G, Chen J, Rosenthal R, Brink R, Chong A S, Klein U, Dinner A R, Singh H, Sciammas R (2013). Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity, 38(5): 918–929
doi: 10.1016/j.immuni.2013.04.009 pmid: 23684984
67 Ouyang X, Zhang R, Yang J, Li Q, Qin L, Zhu C, Liu J, Ning H, Shin M S, Gupta M, Qi C F, He J C, Lira S A, Morse H C 3rd, Ozato K, Mayer L, Xiong H (2011). Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation. Nat Commun, 2: 314
doi: 10.1038/ncomms1311 pmid: 21587231
68 Pathak S, Ma S, Shukla V, Lu R (2013). A role for IRF8 in B cell anergy. J Immunol, 191(12): 6222–6230
doi: 10.4049/jimmunol.1301169 pmid: 24218455
69 Pathak S, Ma S, Trinh L, Eudy J, Wagner K U, Joshi S S, Lu R (2011). IRF4 is a suppressor of c-Myc induced B cell leukemia. PLoS ONE, 6(7): e22628
doi: 10.1371/journal.pone.0022628 pmid: 21818355
70 Pathak S, Ma S, Trinh L, Lu R (2008). A role for interferon regulatory factor 4 in receptor editing. Mol Cell Biol, 28(8): 2815–2824
doi: 10.1128/MCB.01946-07 pmid: 18285461
71 Persson E K, Uronen-Hansson H, Semmrich M, Rivollier A, H?gerbrand K, Marsal J, Gudjonsson S, H?kansson U, Reizis B, Kotarsky K, Agace W W (2013). IRF4 transcription-factor-dependent CD103(+)CD11b(+) dendritic cells drive mucosal T helper 17 cell differentiation. Immunity, 38(5): 958–969
doi: 10.1016/j.immuni.2013.03.009 pmid: 23664832
72 Pillai S, Cariappa A (2009). The follicular versus marginal zone B lymphocyte cell fate decision. Nat Rev Immunol, 9(11): 767–777
doi: 10.1038/nri2656 pmid: 19855403
73 Portal D, Zhou H, Zhao B, Kharchenko P V, Lowry E, Wong L, Quackenbush J, Holloway D, Jiang S, Lu Y, Kieff E (2013). Epstein-Barr virus nuclear antigen leader protein localizes to promoters and enhancers with cell transcription factors and EBNA2. Proc Natl Acad Sci USA, 110(46): 18537–18542
doi: 10.1073/pnas.1317608110 pmid: 24167291
74 Praetorius C, Grill C, Stacey S N, Metcalf A M, Gorkin D U, Robinson K C, Van Otterloo E, Kim R S, Bergsteinsdottir K, Ogmundsdottir M H, Magnusdottir E, Mishra P J, Davis S R, Guo T, Zaidi M R, Helgason A S, Sigurdsson M I, Meltzer P S, Merlino G, Petit V, Larue L, Loftus S K, Adams D R, Sobhiafshar U, Emre N C, Pavan W J, Cornell R, Smith A G, McCallion A S, Fisher D E, Stefansson K, Sturm R A, Steingrimsson E (2013). A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell, 155(5): 1022–1033
doi: 10.1016/j.cell.2013.10.022 pmid: 24267888
75 Pridans C, Holmes M L, Polli M, Wettenhall J M, Dakic A, Corcoran L M, Smyth G K, Nutt S L (2008). Identification of Pax5 target genes in early B cell differentiation. J Immunol, 180(3): 1719–1728
doi: 10.4049/jimmunol.180.3.1719 pmid: 18209069
76 Ramiscal R R, Vinuesa C G (2013). T-cell subsets in the germinal center. Immunol Rev, 252(1): 146–155
doi: 10.1111/imr.12031 pmid: 23405902
77 Rengarajan J, Mowen K A, McBride K D, Smith E D, Singh H, Glimcher L H (2002). Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J Exp Med, 195(8): 1003–1012
doi: 10.1084/jem.20011128 pmid: 11956291
78 Saito M, Gao J, Basso K, Kitagawa Y, Smith P M, Bhagat G, Pernis A, Pasqualucci L, Dalla-Favera R (2007). A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell, 12(3): 280–292
doi: 10.1016/j.ccr.2007.08.011 pmid: 17785208
79 Salaverria I, Philipp C, Oschlies I, Kohler C W, Kreuz M, Szczepanowski M, Burkhardt B, Trautmann H, Gesk S, Andrusiewicz M, Berger H, Fey M, Harder L, Hasenclever D, Hummel M, Loeffler M, Mahn F, Martin-Guerrero I, Pellissery S, Pott C, Pfreundschuh M, Reiter A, Richter J, Rosolowski M, Schwaenen C, Stein H, Trümper L, Wessendorf S, Spang R, Küppers R, Klapper W, Siebert R, the Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe, the German High-Grade Lymphoma Study Group, the Berlin-Frankfurt-Münster-NHL trial group (2011). Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood, 118(1): 139–147
doi: 10.1182/blood-2011-01-330795 pmid: 21487109
80 Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T, Honma K, Matsuyama T, Yui K, Tsujimura T, Standley D M, Nakanishi K, Nakai K, Akira S (2010). The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol, 11(10): 936–944
doi: 10.1038/ni.1920 pmid: 20729857
81 Schlitzer A, McGovern N, Teo P, Zelante T, Atarashi K, Low D, Ho A W, See P, Shin A, Wasan P S, Hoeffel G, Malleret B, Heiseke A, Chew S, Jardine L, Purvis H A, Hilkens C M, Tam J, Poidinger M, Stanley E R, Krug A B, Renia L, Sivasankar B, Ng L G, Collin M, Ricciardi-Castagnoli P, Honda K, Haniffa M, Ginhoux F (2013). IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity, 38(5): 970–983
doi: 10.1016/j.immuni.2013.04.011 pmid: 23706669
82 Sch?nheit J, Kuhl C, Gebhardt M L, Klett F F, Riemke P, Scheller M, Huang G, Naumann R, Leutz A, Stocking C, Priller J, Andrade-Navarro M A, Rosenbauer F (2013). PU.1 level-directed chromatin structure remodeling at the Irf8 gene drives dendritic cell commitment. Cell Reports, 3(5): 1617–1628
doi: 10.1016/j.celrep.2013.04.007 pmid: 23623495
83 Schwickert T A, Tagoh H, Gültekin S, Dakic A, Axelsson E, Minnich M, Ebert A, Werner B, Roth M, Cimmino L, Dickins R A, Zuber J, Jaritz M, Busslinger M (2014). Stage-specific control of early B cell development by the transcription factor Ikaros. Nat Immunol, 15(3): 283–293
doi: 10.1038/ni.2828 pmid: 24509509
84 Sciammas R, Li Y, Warmflash A, Song Y, Dinner A R, Singh H (2011). An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling. Mol Syst Biol, 7(1): 495
doi: 10.1038/msb.2011.25 pmid: 21613984
85 Sciammas R, Shaffer A L, Schatz J H, Zhao H, Staudt L M, Singh H (2006). Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity, 25(2): 225–236
doi: 10.1016/j.immuni.2006.07.009 pmid: 16919487
86 Shaffer A L, Emre N C, Lamy L, Ngo V N, Wright G, Xiao W, Powell J, Dave S, Yu X, Zhao H, Zeng Y, Chen B, Epstein J, Staudt L M (2008). IRF4 addiction in multiple myeloma. Nature, 454(7201): 226–231
doi: 10.1038/nature07064 pmid: 18568025
87 Shaffer, A.L., Emre,N.C., Romesser,P.B., and Staudt,L.M. (2009). IRF4: Immunity. Malignancy! Therapy? Clin Cancer Res, 15: 2954–2961
88 Shou Y, Martelli M L, Gabrea A, Qi Y, Brents L A, Roschke A, Dewald G, Kirsch I R, Bergsagel P L, Kuehl W M (2000). Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci USA, 97(1): 228–233
doi: 10.1073/pnas.97.1.228 pmid: 10618400
89 Shukla V, Ma S, Hardy R R, Joshi S S, Lu R (2013). A role for IRF4 in the development of CLL. Blood, 122(16): 2848–2855
doi: 10.1182/blood-2013-03-492769 pmid: 23926303
90 Simonetti G, Carette A, Silva K, Wang H, De Silva N S, Heise N, Siebel C W, Shlomchik M J, Klein U (2013). IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity. J Exp Med, 210(13): 2887–2902
doi: 10.1084/jem.20131026 pmid: 24323359
91 Slager S L, Rabe K G, Achenbach S J, Vachon C M, Goldin L R, Strom S S, Lanasa M C, Spector L G, Rassenti L Z, Leis J F, Camp N J, Glenn M, Kay N E, Cunningham J M, Hanson C A, Marti G E, Weinberg J B, Morrison V A, Link B K, Call T G, Caporaso N E, Cerhan J R (2011). Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL. Blood, 117(6): 1911–1916
doi: 10.1182/blood-2010-09-308205 pmid: 21131588
92 Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Ulges A, Taube C, Dehzad N, Becker M, Stassen M, Steinborn A, Lohoff M, Schild H, Schmitt E, Bopp T (2010). Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity, 33(2): 192–202
doi: 10.1016/j.immuni.2010.07.014 pmid: 20674401
93 Tailor P, Tamura T, Morse H C 3rd, Ozato K (2008). The BXH2 mutation in IRF8 differentially impairs dendritic cell subset development in the mouse. Blood, 111(4): 1942–1945
doi: 10.1182/blood-2007-07-100750 pmid: 18055870
94 Tamura T, Ozato K (2002). ICSBP/IRF-8: its regulatory roles in the development of myeloid cells. J Interferon Cytokine Res, 22: 145–152
95 Tamura T, Yanai H, Savitsky D, Taniguchi T (2008). The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol, 26(1): 535–584
doi: 10.1146/annurev.immunol.26.021607.090400 pmid: 18303999
96 Thompson E C, Cobb B S, Sabbattini P, Meixlsperger S, Parelho V, Liberg D, Taylor B, Dillon N, Georgopoulos K, Jumaa H, Smale S T, Fisher A G, Merkenschlager M (2007). Ikaros DNA-binding proteins as integral components of B cell developmental-stage-specific regulatory circuits. Immunity, 26(3): 335–344
doi: 10.1016/j.immuni.2007.02.010 pmid: 17363301
97 Tiacci E, D?ring C, Brune V, van Noesel C J, Klapper W, Mechtersheimer G, Falini B, Küppers R, Hansmann M L (2012). Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma. Blood, 120(23): 4609–4620
doi: 10.1182/blood-2012-05-428896 pmid: 22955914
98 Tokoyoda K, Egawa T, Sugiyama T, Choi B I, Nagasawa T (2004). Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity, 20(6): 707–718
doi: 10.1016/j.immuni.2004.05.001 pmid: 15189736
99 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 (2000). MUM1/IRF4 expression as a frequent event in mature lymphoid malignancies. Leukemia, 14(3): 449–456
doi: 10.1038/sj.leu.2401696 pmid: 10720141
100 Tussiwand R, Lee W L, Murphy T L, Mashayekhi M, K C W, Albring J C, Satpathy A T, Rotondo J A, Edelson B T, Kretzer N M, Wu X, Weiss L A, Glasmacher E, Li P, Liao W, Behnke M, Lam S S, Aurthur C T, Leonard W J, Singh H, Stallings C L, Sibley L D, Schreiber R D, Murphy K M (2012). Compensatory dendritic cell development mediated by BATF-IRF interactions. Nature, 490(7421): 502–507
doi: 10.1038/nature11531 pmid: 22992524
101 Vander Lugt B, Khan A A, Hackney J A, Agrawal S, Lesch J, Zhou M, Lee W P, Park S, Xu M, DeVoss J, Spooner C J, Chalouni C, Delamarre L, Mellman I, Singh H (2014). Transcriptional programming of dendritic cells for enhanced MHC class II antigen presentation. Nat Immunol, 15(2): 161–167
doi: 10.1038/ni.2795 pmid: 24362890
102 Wang H, Lee C H, Qi C, Tailor P, Feng J, Abbasi S, Atsumi T, Morse H C 3rd (2008). IRF8 regulates B-cell lineage specification, commitment, and differentiation. Blood, 112(10): 4028–4038
doi: 10.1182/blood-2008-01-129049 pmid: 18799728
103 Wang L, Ning S (2013). Interferon regulatory factor 4 is activated through c-Src-mediated tyrosine phosphorylation in virus-transformed cells. J Virol, 87(17): 9672–9679
doi: 10.1128/JVI.01435-13 pmid: 23804646
104 Wen L, Shinton S A, Hardy R R, Hayakawa K (2005). Association of B-1 B cells with follicular dendritic cells in spleen. J Immunol, 174(11): 6918–6926
doi: 10.4049/jimmunol.174.11.6918 pmid: 15905534
105 Willis S N, Good-Jacobson,K L, Curtis J, Light A, Tellier J, Shi W, Smyth G K, Tarlinton D M, Belz G T, Corcoran L M, Kallies A, Nutt S L (2014). Transcription factor IRF4 regulates germinal center cell formation through a B cell-intrinsic mechanism. J Immunol, doi: 10.4049/jimmunol.1303216
106 Wu C Y, Maeda H, Contursi C, Ozato K, Seder R A (1999). Differential requirement of IFN consensus sequence binding protein for the production of IL-12 and induction of Th1-type cells in response to IFN-gamma. J Immunol, 162(2): 807–812
pmid: 9916702
107 Xiang M, Wang L, Guo S, Lu Y Y, Lei H, Jiang D S, Zhang Y, Liu Y, Zhou Y, Zhang X D, Li H (2014). Interferon regulatory factor 8 protects against cerebral ischaemic-reperfusion injury. J Neurochem, doi: 10.1111/jnc.12682
pmid: 24528256
108 Xu H, Zhu J, Smith S, Foldi J, Zhao B, Chung A Y, Outtz H, Kitajewski J, Shi C, Weber S, Saftig P, Li Y, Ozato K, Blobel C P, Ivashkiv L B, Hu X (2012). Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat Immunol, 13(7): 642–650
doi: 10.1038/ni.2304 pmid: 22610140
109 Yang Y, Shaffer A L 3rd, Emre N C, Ceribelli M, Zhang M, Wright G, Xiao W, Powell J, Platig J, Kohlhammer H, Young R M, Zhao H, Yang Y, Xu W, Buggy J J, Balasubramanian S, Mathews L A, Shinn P, Guha R, Ferrer M, Thomas C, Waldmann T A, Staudt L M (2012). Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell, 21(6): 723–737
doi: 10.1016/j.ccr.2012.05.024 pmid: 22698399
110 Yao S, Buzo B F, Pham D, Jiang L, Taparowsky E J, Kaplan M H, Sun J (2013). Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation. Immunity, 39(5): 833–845
doi: 10.1016/j.immuni.2013.10.007 pmid: 24211184
111 Yoshida Y, Yoshimi R, Yoshii H, Kim D, Dey A, Xiong H, Munasinghe J, Yazawa I, O’Donovan M J, Maximova O A, Sharma S, Zhu J, Wang H, Morse H C 3rd, Ozato K (2014). The transcription factor IRF8 activates integrin-mediated TGF-β signaling and promotes neuroinflammation. Immunity, 40(2): 187–198
doi: 10.1016/j.immuni.2013.11.022 pmid: 24485804
112 Zhang S M, Gao L, Zhang X F, Zhang R, Zhu L H, Wang P X, Tian S, Yang D, Chen K, Huang L, Zhang X D, Li H (2014). Interferon regulatory factor 8 modulates phenotypic switching of smooth muscle cells by regulating the activity of myocardin. Mol Cell Biol, 34(3): 400–414
doi: 10.1128/MCB.01070-13 pmid: 24248596
113 Zheng Y, Chaudhry A, Kas A, deRoos P, Kim J M, Chu T T, Corcoran L, Treuting P, Klein U, Rudensky A Y (2009). Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature, 458(7236): 351–356
doi: 10.1038/nature07674 pmid: 19182775
[1] Iouri CHEPELEV, Xin CHEN. Alternative splicing switching in stem cell lineages[J]. Front Biol, 2013, 8(1): 50-59.
[2] Kazuhiro TANAKA, Nikhat J. SIDDIQI, Abdullah S. ALHOMIDA, Akhlaq A. FAROOQUI, Wei-Yi ONG. Differential regulation of cPLA2 and iPLA2 expression in the brain[J]. Front Biol, 2012, 7(6): 514-521.
[3] Gabriel J. SWENSON, J. STOCHASTIC, Franklyn F. BOLANDER, Jr., Richard A. LONG. Acid stress response in environmental and clinical strains of enteric bacteria[J]. Front Biol, 2012, 7(6): 495-505.
[4] Jinbiao MA, Ying HUANG, . Post-transcriptional regulation of miRNA biogenesis and functions[J]. Front. Biol., 2010, 5(1): 32-40.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed