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The Unsolved Puzzle of C-Rel in B Cell Lymphoma

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The Unsolved Puzzle of C-Rel in B Cell Lymphoma cancers Review The Unsolved Puzzle of c-Rel in B Cell Lymphoma 1, , 1,2, Maike Kober-Hasslacher * y and Marc Schmidt-Supprian * 1 Institute of Experimental Hematology, School of Medicine, Technical University Munich, Ismaninger Straße 22, 81675 Munich, Germany 2 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany * Correspondence: [email protected] (M.K.-H.); [email protected] (M.S.-S.) Current address: Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany. y Received: 23 May 2019; Accepted: 29 June 2019; Published: 4 July 2019 Abstract: Aberrant constitutive activation of Rel/NF-κB transcription factors is a hallmark of numerous cancers. Of the five Rel family members, c-Rel has the strongest direct links to tumorigenesis. c-Rel is the only member that can malignantly transform lymphoid cells in vitro. Furthermore, c-Rel is implicated in human B cell lymphoma through the frequent occurrence of REL gene locus gains and amplifications. In normal physiology, high c-Rel expression predominates in the hematopoietic lineage and a diverse range of stimuli can trigger enhanced expression and activation of c-Rel. Both expression and activation of c-Rel are tightly regulated on multiple levels, indicating the necessity to keep its functions under control. In this review we meta-analyze and integrate studies reporting gene locus aberrations to provide an overview on the frequency of REL gains in human B cell lymphoma subtypes, namely follicular lymphoma, diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, and classical Hodgkin lymphoma. We also summarize current knowledge on c-Rel expression and protein localization in these human B cell lymphomas and discuss the co-amplification of BCL11A with REL. In addition, we highlight and illustrate key pathways of c-Rel activation and regulation with a specific focus on B cell biology. Keywords: c-Rel; NF-κB; B cells; REL gene locus amplification; lymphoma; FL; DLBCL; PMBCL; cHL 1. Introduction: c-Rel Is the NF-κB Family Transcription Factor with the Strongest Link to Human Lymphoma The transcription factor c-Rel is one of five members of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) family of transcription factors. In contrast to other ubiquitously expressed Rel/NF-κB family members [1], high c-Rel expression has been predominantly detected in the hematopoietic lineage, under healthy conditions [2]. The particular importance of c-Rel function in the immune system, in general, and in B cells, in particular, was revealed through the analyses of conventional and conditional c-Rel knockout mice [3–6]. During steady state conditions, dimers of NF-κB proteins are kept inactive sequestered in the cytoplasm through interaction with inhibitor of κB (IκB) proteins. Various upstream stimuli mark these IκB proteins for proteasomal degradation allowing homo- or heterodimeric NF-κB dimers, including c-Rel complexes, to translocate to the nucleus to reprogram gene expression [7,8]. The c-Rel/NF-κB target gene space is characterized by redundancy through substantial overlap and compensation between the NF-κB subunits [1]. Key c-Rel/NF-κB targets include genes encoding survival factors, regulators of cell cycle, and proliferation, as well as mediators of immune cell signaling [9]. Given these groups of target genes, it is not surprising that aberrant constitutive NF-κB activation is a hallmark of numerous cancers, including lymphoid tumors [10–12]. Intriguingly, to date, c-Rel is the only member of the NF-κB family for which direct Cancers 2019, 11, 941; doi:10.3390/cancers11070941 www.mdpi.com/journal/cancers Cancers 2019, 11, x 2 of 25 Cancers 2019, 11, 941 2 of 26 hallmark of numerous cancers, including lymphoid tumors [10–12]. Intriguingly, to date, c-Rel is the only member of the NF-κB family for which direct transforming activity has been shown: Retroviral transformingexpression of activityboth human has been and shown:mouse c-Rel Retroviral led to expression malignant oftransformation both human andof chicken mouse spleen c-Rel led cells to malignantin vitro [13]. transformation of chicken spleen cells in vitro [13]. In thisthis review,review, we we discuss discuss literature literature that that lays lays the the foundation foundation for for the the current current picture picture of c-Rel’s of c-Rel’s role inrole human in human B cell B lymphomas. cell lymphomas. We begin We begin with an with introduction an introduction of c-Rel of signaling c-Rel signaling by highlighting by highlighting aspects ofaspects c-Rel of activation c-Rel activation and regulation, and regulation, particularly particularly in B cells. in We B thencells. focus We then on the focus frequent on the occurrence frequent ofoccurrenceREL gene of locus REL gainsgene andlocus amplifications gains and amplifications in human B in cell human lymphoma B celland lymphoma provide and an overview provide an of reportedoverview gene of reported locus aberrations gene locus in aberrations relevant human in relevant lymphoma human subtypes. lymphoma Furthermore, subtypes. we Furthermore, summarize publicationswe summarize analyzing publications c-Rel expressionanalyzing andc-Rel protein expression localization and protein in these localization human B cell in lymphomasthese human and B discusscell lymphomas the co-amplification and discuss oftheBCL11A co-amplificationwith REL. of BCL11A with REL. 2. Control of c-Rel Expression, Abundance, and Activation in B Cells The humanhumanREL RELgene gene locus locus on on chromosome chromosome 2 encodes 2 encodes the c-Relthe c-Rel protein protein with awith length a length of 587 aminoof 587 acidsamino and acids an approximateand an approximate molecular molecular weight of weight 65 kDa of [14 65,15 kDa] (Figure [14,15]1). (Figure The first 1). 300 The amino first acids 300 amino at the c-Relacids aminoat the terminusc-Rel amino constitute terminus the constitute highly conserved the highly Rel homologyconserved domainRel homology (RHD), domain which is (RHD), shared withwhich other is shared NF-κB familywith other members. NF-κB The family RHD members. is involved The in DNA-binding,RHD is involved dimerization, in DNA-binding, inhibitor interaction,dimerization, and inhibitor nuclear interaction, localization and [7]. nuclear At its carboxy localization terminus, [7]. c-RelAt its contains carboxy aterminus, transactivation c-Rel domaincontains (TAD), a transactivation which harbors domain twosubdomains (TAD), which referred harbors to astwo TAD1 subdomains and TAD2 referred that map to to as amino TAD1 acids and 425–490TAD2 that and map 518–587, to amino respectively acids 425–490 [9,16,17 ].and The 518–587, protein sequencerespectively upstream [9,16,17]. of the The TAD protein at amino sequence acids 323–422upstream was of definedthe TAD as at the amino Rel inhibitory acids 323–422 domain was (RID) defined as mutants as the lacking Rel inhibitory this region domain show enhanced(RID) as transactivationmutants lacking and this DNA-binding region show inenhanced vitro [15 ].transactivation c-Rel carries aand nuclear DNA-binding localization in signalvitro [15]. (NLS) c-Rel but nocarries nuclear a nuclear export localization signal (NES) sign [18al,19 (NLS)]. Remarkably, but no nuclear two alternativeexport signal versions (NES) of[18,19]. the REL Remarkably,transcript weretwo alternative identifiedin versions human Bof cell the lymphoma: REL transcript First, were a REL identifiedtranscript in containing human Ban cell exonized lymphoma: Alu elementFirst, a betweenREL transcript exon 8 andcontaining 9 that could an exonized encode a proteinAlu elem ofent 619 aminobetween acids exon [20 ],8 second,and 9 that a lymphoma-specific could encode a spliceprotein variant of 619 ofamino human acids c-Rel [20], lacking second, the a entirelymphoma-specific exon 9 (amino splice acids variant 308–330) of withhuman a higher c-Rel inlacking vitro transactivationthe entire exon activity9 (amino [15 acids]. 308–330) with a higher in vitro transactivation activity [15]. Figure 1. Human c-Rel protein domains—schematic illustration.illustration. Amino acid start and end points of represented protein domainsdomains areare indicatedindicated byby numbersnumbers belowbelow thethe scheme.scheme. The position of the amino acid sequence encoded by exon 9 (aa(aa 308–330)308–330) isis highlightedhighlighted byby dotteddotted lines.lines. RHD, Rel homology domain; RID, Rel inhibitory domain; TAD, transactivation domain; NLS, nuclear localization signal. This figurefigure is basedbased onon [[9,15].9,15]. Other references assignassign the RHD to aa 8–290 [[21]21] or aa 8–2978–297 (UniProt database, UniProtKB, Q04864 RELREL (human),(human), www.uniprot.orgwww.uniprot.org).). In the mouse, under normal physiological conditions, high expression of c-Rel is predominant In the mouse, under normal physiological conditions, high expression of c-Rel is predominant in the hematopoietic system [2]. c-Rel expression is regulated by transcription factors of the in the hematopoietic system [2]. c-Rel expression is regulated by transcription factors of the PU.1/SpiB family [22,23] as well as through NF-κB transcription factors, including c-Rel itself [24]. PU.1/SpiB family [22,23] as well as through NF-κB transcription factors, including c-Rel itself [24]. The autoregulation of c-Rel and other NF-κB family members, including a database mapping of the The autoregulation of c-Rel and other NF-κB family members, including a database mapping of the binding sites for RelA, RelB, and c-Rel itself within the c-Rel promoter has been recently reviewed [25]. binding sites for RelA, RelB, and c-Rel itself within the c-Rel promoter has been recently reviewed c-Rel is highly abundant in resting splenic B cells and its expression is dramatically upregulated [25]. upon activation. This is in line with a predominant NF-κB dimer composition of c-Rel and p50 c-Rel is highly abundant in resting splenic B cells and its expression is dramatically upregulated in mature B cells [26].
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