| Note | |
| | |
| Entity | 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/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. |
| | |
| | |
| Entity | 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/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. |
| | |
| | |
| Entity | 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 | 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 | 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 | 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 | 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 | 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 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. |
| | |
| | |
| Entity | 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. |
| | |
| IRF-4 functions as a tumor suppressor in early B-cell development. |
| Acquaviva J, Chen X, Ren R. |
| Blood. 2008 Nov 1;112(9):3798-806. doi: 10.1182/blood-2007-10-117838. Epub 2008 Aug 19. |
| PMID 18713947 |
| |
| Expression of MUM1/IRF4 correlates with clinical outcome in patients with B-cell chronic lymphocytic leukemia. |
| Chang CC, Lorek J, Sabath DE, Li Y, Chitambar CR, Logan B, Kampalath B, Cleveland RP. |
| Blood. 2002 Dec 15;100(13):4671-5. Epub 2002 Aug 1. |
| PMID 12393648 |
| |
| A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. |
| Di Bernardo MC, Crowther-Swanepoel D, Broderick P, Webb E, Sellick G, Wild R, Sullivan K, Vijayakrishnan J, Wang Y, Pittman AM, Sunter NJ, Hall AG, Dyer MJ, Matutes E, Dearden C, Mainou-Fowler T, Jackson GH, Summerfield G, Harris RJ, Pettitt AR, Hillmen P, Allsup DJ, Bailey JR, Pratt G, Pepper C, Fegan C, Allan JM, Catovsky D, Houlston RS. |
| Nat Genet. 2008 Oct;40(10):1204-10. doi: 10.1038/ng.219. Epub 2008 Aug 31. |
| PMID 18758461 |
| |
| Transcriptional control of adipose lipid handling by IRF4. |
| Eguchi J, Wang X, Yu S, Kershaw EE, Chiu PC, Dushay J, Estall JL, Klein U, Maratos-Flier E, Rosen ED. |
| Cell Metab. 2011 Mar 2;13(3):249-59. doi: 10.1016/j.cmet.2011.02.005. |
| PMID 21356515 |
| |
| Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. |
| Falini B, Mason DY. |
| Blood. 2002 Jan 15;99(2):409-26. Review |
| PMID 11781220 |
| |
| Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas. |
| Feldman AL, Law M, Remstein ED, Macon WR, Erickson LA, Grogg KL, Kurtin PJ, Dogan A. |
| Leukemia. 2009 Mar;23(3):574-80. doi: 10.1038/leu.2008.320. Epub 2008 Nov 6. |
| PMID 18987657 |
| |
| A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. |
| Glasmacher E, Agrawal S, Chang AB, Murphy TL, Zeng W, Vander Lugt B, Khan AA, Ciofani M, Spooner CJ, Rutz S, Hackney J, Nurieva R, Escalante CR, Ouyang W, Littman DR, Murphy KM, Singh H. |
| Science. 2012 Nov 16;338(6109):975-80. doi: 10.1126/science.1228309. Epub 2012 Sep 13. |
| PMID 22983707 |
| |
| Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25. |
| Grossman A, Mittrucker HW, Nicholl J, Suzuki A, Chung S, Antonio L, Suggs S, Sutherland GR, Siderovski DP, Mak TW. |
| Genomics. 1996 Oct 15;37(2):229-33. |
| PMID 8921401 |
| |
| Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS. |
| Honma K, Udono H, Kohno T, Yamamoto K, Ogawa A, Takemori T, Kumatori A, Suzuki S, Matsuyama T, Yui K. |
| Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16001-6. Epub 2005 Oct 21. |
| PMID 16243976 |
| |
| Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. |
| Iida S, Rao PH, Butler M, Corradini P, Boccadoro M, Klein B, Chaganti RS, Dalla-Favera R. |
| Nat Genet. 1997 Oct;17(2):226-30. |
| PMID 9326949 |
| |
| MUM1/IRF4 expression is an unfavorable prognostic factor in B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). |
| Ito M, Iida S, Inagaki H, Tsuboi K, Komatsu H, Yamaguchi M, Nakamura N, Suzuki R, Seto M, Nakamura S, Morishima Y, Ueda R. |
| Jpn J Cancer Res. 2002 Jun;93(6):685-94. |
| PMID 12079517 |
| |
| Interferon regulatory factor 4 and 8 in B-cell development. |
| Lu R. |
| Trends Immunol. 2008 Oct;29(10):487-92. doi: 10.1016/j.it.2008.07.006. Epub 2008 Sep 3. (REVIEW) |
| PMID 18775669 |
| |
| Repression of IRF-4 target genes in human T cell leukemia virus-1 infection. |
| Mamane Y, Grandvaux N, Hernandez E, Sharma S, Innocente SA, Lee JM, Azimi N, Lin R, Hiscott J. |
| Oncogene. 2002 Oct 3;21(44):6751-65. |
| PMID 12360402 |
| |
| Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. |
| Mittrucker HW, Matsuyama T, Grossman A, Kundig TM, Potter J, Shahinian A, Wakeham A, Patterson B, Ohashi PS, Mak TW. |
| Science. 1997 Jan 24;275(5299):540-3. |
| PMID 8999800 |
| |
| Negative regulation of Toll-like-receptor signaling by IRF-4. |
| Negishi H, Ohba Y, Yanai H, Takaoka A, Honma K, Yui K, Matsuyama T, Taniguchi T, Honda K. |
| Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15989-94. Epub 2005 Oct 19. |
| PMID 16236719 |
| |
| 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, Yamamoto K, Imaizumi Y, Kohno T, Matsuyama T. |
| Mol Immunol. 2004 Jul;41(9):855-61. |
| PMID 15261457 |
| |
| Down-regulation of interferon regulatory factor 4 gene expression in leukemic cells due to hypermethylation of CpG motifs in the promoter region. |
| Ortmann CA, Burchert A, Holzle K, Nitsche A, Wittig B, Neubauer A, Schmidt M. |
| Nucleic Acids Res. 2005 Dec 7;33(21):6895-905. Print 2005. |
| PMID 16396836 |
| |
| A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. |
| Praetorius C, Grill C, Stacey SN, Metcalf AM, Gorkin DU, Robinson KC, Van Otterloo E, Kim RS, Bergsteinsdottir K, Ogmundsdottir MH, Magnusdottir E, Mishra PJ, Davis SR, Guo T, Zaidi MR, Helgason AS, Sigurdsson MI, Meltzer PS, Merlino G, Petit V, Larue L, Loftus SK, Adams DR, Sobhiafshar U, Emre NC, Pavan WJ, Cornell R, Smith AG, McCallion AS, Fisher DE, Stefansson K, Sturm RA, Steingrimsson E. |
| Cell. 2013 Nov 21;155(5):1022-33. doi: 10.1016/j.cell.2013.10.022. |
| PMID 24267888 |
| |
| The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. |
| 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 DM, Nakanishi K, Nakai K, Akira S. |
| Nat Immunol. 2010 Oct;11(10):936-44. doi: 10.1038/ni.1920. Epub 2010 Aug 22. |
| PMID 20729857 |
| |
| IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. |
| Schlitzer A, McGovern N, Teo P, Zelante T, Atarashi K, Low D, Ho AW, See P, Shin A, Wasan PS, Hoeffel G, Malleret B, Heiseke A, Chew S, Jardine L, Purvis HA, Hilkens CM, Tam J, Poidinger M, Stanley ER, Krug AB, Renia L, Sivasankar B, Ng LG, Collin M, Ricciardi-Castagnoli P, Honda K, Haniffa M, Ginhoux F. |
| Immunity. 2013 May 23;38(5):970-83. doi: 10.1016/j.immuni.2013.04.011. |
| PMID 23706669 |
| |
| IRF4: Immunity. Malignancy! Therapy? |
| Shaffer AL, Emre NC, Romesser PB, Staudt LM. |
| Clin Cancer Res. 2009 May 1;15(9):2954-61. doi: 10.1158/1078-0432.CCR-08-1845. Epub 2009 Apr 21. (REVIEW) |
| PMID 19383829 |
| |
| A role for IRF4 in the development of CLL. |
| Shukla V, Ma S, Hardy RR, Joshi SS, Lu R. |
| Blood. 2013 Oct 17;122(16):2848-55. doi: 10.1182/blood-2013-03-492769. Epub 2013 Aug 7. |
| PMID 23926303 |
| |
| IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity. |
| Simonetti G, Carette A, Silva K, Wang H, De Silva NS, Heise N, Siebel CW, Shlomchik MJ, Klein U. |
| J Exp Med. 2013 Dec 16;210(13):2887-902. doi: 10.1084/jem.20131026. Epub 2013 Dec 9. |
| PMID 24323359 |
| |
| MUM1/IRF4 expression as a frequent event in mature lymphoid malignancies. |
| 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. |
| Leukemia. 2000 Mar;14(3):449-56. |
| PMID 10720141 |
| |
| Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. |
| Yang Y, Shaffer AL 3rd, Emre NC, Ceribelli M, Zhang M, Wright G, Xiao W, Powell J, Platig J, Kohlhammer H, Young RM, Zhao H, Yang Y, Xu W, Buggy JJ, Balasubramanian S, Mathews LA, Shinn P, Guha R, Ferrer M, Thomas C, Waldmann TA, Staudt LM. |
| Cancer Cell. 2012 Jun 12;21(6):723-37. doi: 10.1016/j.ccr.2012.05.024. |
| PMID 22698399 |
| |
| Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. |
| Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu TT, Corcoran L, Treuting P, Klein U, Rudensky AY. |
| Nature. 2009 Mar 19;458(7236):351-6. doi: 10.1038/nature07674. Epub 2009 Feb 1. |
| PMID 19182775 |
| |
