A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway

Praetorius, Christian; Grill, Christine; Stacey, Simon; Metcalf, Alexander M.; Gorkin, David U.; Robinson, Kathleen C.; Otterloo, Eric Van; Kim, Reuben S.Q.; Bergsteinsdóttir, Kristín; Ögmundsdóttir, Margrét H.; Magnúsdóttir, Erna; Mishra, Pravin J.; Davis, Sean; Guo, Theresa; Zaidi, M. Raza; Helgason, Agnar; Sigurdsson, Martin I.; Meltzer, Paul S.; Merlino, Glenn; Petit, Valérie; Larue, Lionel; Loftus, Stacie K.; Adams, David R.; Sobhiafshar, Ulduz; Emre, N. C. Tolga; Pavan, William J.; Cornell, Robert A.; Smith, Aaron G.; McCallion, Andrew S.; Fisher, David E.; Stefánsson, Kári; Sturm, Richard A.; Steingrímsson, Eiríkur

doi:10.1016/j.cell.2013.10.022

Cited by 196 publications

(215 citation statements)

References 67 publications

(79 reference statements)

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“…18,65,66 Our data do not establish whether these genetic findings directly contribute to IRF4 expression in PTCLs. For example, IRF4 CNAs in IRF4-positive PTCLs might relate to increased polysomy rather than focal IRF4 gains.…”

Section: Discussioncontrasting

confidence: 59%

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Boddicker

Kip

Xing

et al. 2015

Blood

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• The NF-kB subunits p52 and RelB increase IRF4 promoter activity and expression in PTCL cells.• A positive feedback loop involving CD30, NF-kB, and IRF4 drives PTCL cell proliferation and can be blocked by NF-kB inhibitors.Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor kB (NF-kB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-kB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-kB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-kB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs. (Blood. 2015; 125(20):3118-3127) Introduction Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas (NHLs) characterized by poor overall survival rates. [1][2][3] Most patients are treated with anthracycline-based chemotherapy regimens originally designed for B-cell lymphomas. Five-year overall survival rates vary somewhat by subtype but average ;35%. The possibility of individualized targeted therapy holds promise, but advances have been hindered by the fact that few therapeutic targets have been identified and validated in PTCLs. Our group's approach to this challenge has been to characterize the genetics of PTCLs to identify novel biomarkers and therapeutic targets. We have focused particularly on chromosomal translocations, which have played a major role in identifying diagnostic, prognostic, and theranostic biomarkers in hematologic neoplasms in general (eg, BCR-ABL) and PTCLs specifically (ALK rearrangements). 4,5 We previously discovered a recurrent translocation in PTCL, t(6;14)(p25.3;q11.2), that juxtaposes the interferon regulatory factor-4 (IRF4) and T-cell receptor-a (TRA) genes and is associated with increased IRF4 expression. 6 Because TRA translocation partners typically function as oncogenes in T-cell malignancies, we postulated that IRF4 plays an oncogenic role in PTCLs.7 IRF4 is a tightly regulated transcription factor involved in growth and differentiation of normal T and B lymp...

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Section: Discussioncontrasting

confidence: 59%

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Boddicker

Kip

Xing

et al. 2015

Blood

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“…This rs12203592 * T polymorphism was found to be strongly associated with darker hair colour, hair greying, lighter eye colour and reduced skin tanning response to sunlight [19,73,75] and it lies within an enhancer element that drives IRF4 transcription in melanocytes. The rs12203592 * T allele impairs binding of the TFAP2A transcription factor that, together with the melanocyte master regulator MITF, regulates the activity of the enhancer [76] . It has also been found that MITF directly or indirectly regulates IRF4 expression, and that TYR expression depends on IRF4 protein [76] .…”

Section: Irf4: a Gene For Tanning And Naevimentioning

confidence: 99%

“…The rs12203592 * T allele impairs binding of the TFAP2A transcription factor that, together with the melanocyte master regulator MITF, regulates the activity of the enhancer [76] . It has also been found that MITF directly or indirectly regulates IRF4 expression, and that TYR expression depends on IRF4 protein [76] . Asian and African populations are fixed for the rs12203592 * C allele, being monoallelic, with only European populations possessing the rs12203592 * T at around 17% allele frequency.…”

Section: Irf4: a Gene For Tanning And Naevimentioning

confidence: 99%

Skin Pigmentation Genetics for the Clinic

Ainger

Jagirdar²,

Lee³

et al. 2017

Dermatology

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Human pigmentation characteristics play an important role in the effects of sun exposure, skin cancer induction and disease outcomes. Several of the genes most important for this diversity are involved in the regulation and distribution of melanin pigmentation or enzymes involved in melanogenesis itself within the melanocyte cell present in the skin, hair and eyes. The single nucleotide polymorphisms and extended haplotypes within or surrounding these genes have been identified as risk factors for skin cancer, in particular, melanoma. These same polymorphisms have been under selective pressure leading towards lighter pigmentation in Europeans in the last 5,000-20,000 years that have driven the increase in frequency in modern populations. Although pigmentation is a polygenic trait, due to interactive and quantitative gene effects, strong phenotypic associations are readily apparent for these major genes. However, predictive value and utility are increased when considering gene polymorphism interactions. In melanoma, an increased penetrance is found in cases when pigmentation gene risk alleles such as MC1R variants are coincident with mutation of higher-risk melanoma genes including CDKN2A, CDK4 and MITF E318K, demonstrating an interface between the pathways for pigmentation, naevogenesis and melanoma. The clinical phenotypes associated with germline changes in pigmentation and naevogenic genes must be understood by clinicians, and will be of increasing relevance to dermatologists, as genomics is incorporated into the delivery of personalised medicine.

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“…IRF4 and IRF8 were initially thought to be exclusively expressed in cells of immune lineages. However, recent reports have also identified IRF4 and/orIRF8 expression in melanocytes, adipocytes, smooth muscles, cardiac muscles and neurons where they perform diverse functions (Eguchi et al, 2011; Guo et al, 2014; Jiang et al, 2013; Jiang et al, 2014a; Praetorius et al, 2013; Xiang et al, 2014; Yoshida et al, 2014; Zhang et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

IRF4 and IRF8: governing the virtues of B lymphocytes

Shukla

2014

Front. Biol.

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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.

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A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway

Cited by 196 publications

References 67 publications

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Skin Pigmentation Genetics for the Clinic

IRF4 and IRF8: governing the virtues of B lymphocytes

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