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RESEARCHARTICLEOpenAccessCharacteristicsofCARMA1-BCL10-MALT1-A20-NF-κBexpressioninTcell-acutelymphocyticleukemiaYuMa1,ZiweiLiao1,YiXu1,ZiyunZhong2,XuWang1,3,FanZhang1,ShaohuaChen1,LijianYang1,GengxinLuo1,XinHuang4,SumingHuang5,XiuliWu1*andYangqiuLi1,3*AbstractBackground:KnowledgeoftheoncogenicsignalingpathwaysofT-cellacutelymphoblasticleukemia(T-ALL)remainslimited.
ConstitutiveaberrantactivationofthenuclearfactorkappaB(NF-κB)signalingpathwayhasbeendetectedinvariouslymphoidmalignanciesandplaysakeyroleinthedevelopmentofthesecarcinomas.
Thezincfinger-containingprotein,A20,isacentralregulatorofmultipleNF-κB-activatingsignalingcascades.
A20isfrequentlyinactivatedbydeletionsand/ormutationsinseveralB-andT-celllymphomasubtypes.
However,fewA20mutationsandpolymorphismshavebeenreportedinT-ALL.
Thus,itisofinteresttoanalyzetheexpressioncharacteristicsofA20anditsregulatingfactors,includingupstreamregulatorsandtheCBMcomplex,whichincludesCARMA1,BCL10,andMALT1.
Methods:TheexpressionlevelsofCARMA1,BCL10,MALT1,A20,andNF-κBweredetectedinperipheralbloodmononuclearcells(PBMCs)from21patientswithnewlydiagnosedT-ALLusingreal-timePCR,andcorrelationsbetweentheaberrantexpressionofthesegenesinT-ALLwasanalyzed.
Sixteenhealthyindividuals,including10malesand6females,servedascontrols.
Results:SignificantlylowerA20expressionwasfoundinT-ALLpatients(median:4.
853)comparedwithhealthyindividuals(median:8.
748;P=0.
017),andsignificantlyincreasedexpressionlevelsofCARMA1(median:2.
916;P=0.
034),BCL10(median:0.
285;P=0.
033),andMALT1(median:1.
201;P=0.
010)werefoundinT-ALLcomparedwiththehealthyindividuals(median:1.
379,0.
169,and0.
677,respectively).
Incontrast,overexpressionofNF-κB(median:0.
714)wasfoundinT-ALLcomparedwithhealthyindividuals(median:0.
335;P=0.
001).
AnegativecorrelationbetweentheMALT1andA20expressionlevelsandapositivecorrelationbetweenCARMA1andBCL10werefoundinT-ALLandhealthyindividuals.
However,nonegativecorrelationwasfoundbetweenA20andNF-κBandtheMALT1andNF-κBexpressionlevelintheT-ALLgroup.
Conclusions:WecharacterizedtheexpressionoftheCARMA-BCL10-MALT1-A20-NF-κBpathwaygenesinT-ALL.
OverexpressionofCARMA-BCL10-MALTinT-ALLmaycontributetotheconstitutivecleavageandinactivationofA20,whichenhancesNF-κBsignalingandmayberelatedtoT-ALLpathogenesis.
Keywords:A20,CARMA1-BCL10-MALT1,T-cellacutelymphoblasticleukemia*Correspondence:siulier@163.
com;yangqiuli@hotmail.
comEqualcontributors1InstituteofHematology,JinanUniversity,Guangzhou510632,China3KeyLaboratoryforRegenerativeMedicineofMinistryofEducation,JinanUniversity,Guangzhou510632,ChinaFulllistofauthorinformationisavailableattheendofthearticleEUROPEANJOURNALOFMEDICALRESEARCH2014Maetal.
;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/4.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycredited.
TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.
org/publicdomain/zero/1.
0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestated.
Maetal.
EuropeanJournalofMedicalResearch2014,19:62http://www.
eurjmedres.
com/content/19/1/62BackgroundT-cellacutelymphoblasticleukemia(T-ALL),whichac-countsfor15%ofallnewlydiagnosedALLcasesinchil-drenand20to25%ofALLcasesinadults,resultsfromclonalmalignantT-cellproliferation,isanaggressivemalignancythatdoesnotrespondwelltochemotherapy,andhaspoorerprognosisthanitsB-cellcounterpart[1-3].
ThecellularbiologyandpathogenesisofT-ALLarerelativelycomplex,andthesemightberelatedtothedifferentoriginalmalignantT-cellclone,e.
g.
,T-ALLcaseswithtwomalignantT-cellclonesoramono-malignantT-cellclonehavedifferentgeneexpressionpatterns[4-6].
IthasalsobeenreportedthattheacuteandlymphomasubtypesofadultT-cellleukemia/lymphomasaregenomi-callydistinct;thus,theymaydeveloptumorsviadifferentgeneticpathwaysassuggestedbycomparativeanalysisoftheirgenomicprofiles[7].
Complexacquiredgeneticaber-rationsincludechromosomaltranslocations,andgenere-arrangementsandmutations,resultingintheabnormalexpressionofoncogenessuchasNotch1,TAL1(T-cellacutelymphoblasticleukemia1),andBCL11B(B-cellchroniclymphocyticleukemia/lymphoma11B),whichmaybeassociatedwithadvanceddiseaseandresistancetotreatment[8-14].
Incontrast,abnormalT-cellactiva-tionisvitalforcellulartransformation,andvarioussig-nalingpathwaysaretriggeredbytheT-cellreceptorthatplaykeyrolesincontrollingT-cellactivation.
Forex-ample,recentfindingsdefineMALT1(mucosa-associ-ated-lymphoid-tissuelymphoma-translocationgene1)asaproteinwithproteolyticactivitythatcontrolsT-cellactivationbyregulatingkeymoleculesinT-cellreceptor(TCR)-inducedsignalingpathways[15].
Moreover,anumberofstudieshaveshownthatinA20(tumorne-crosisfactor-α-inducedprotein3;TNFAIP3),whichisanuclearfactorkappaB(NF-κB)negativeregulator,gen-eticalterationsarefrequentlyfoundinlymphomas,sug-gestingthattheremaybealinkbetweenthealteredimmuneresponseandleukemogenesis[16-23].
Further-more,itwasshownthatTCRstimulationinducestherecruitmentofA20intoaCBMcomplexcontainingCARMA1(caspase-recruitmentdomain(CARD)contain-ingmembrane-associatedguanylatekinaseprotein1,alsocalledCARD11),adaptorproteinBcl-10(B-celllymphoma10),andMALT1(paracaspasemucosa-associatedlymph-oidtissuelymphomatranslocationgene1),leadingtoMALT1-mediatedA20processing.
MALT1cleaveshumanA20afterarginine439andimpairsitsNF-κB-inhibitoryfunction.
A20isasubstrateofMALT1,underscoringtheimportanceofMALT1proteolyticactivityinthe'finetun-ing'ofTCRsignaling[24].
A20isfrequentlyinactivatedbydeletionsand/ormu-tationsinseverallymphomasubtypesincludingB-andT-cells[16-22].
Recently,bi-andmonoallelicA20dele-tionsinahighproportionofSezarysyndromepatientsandabiallelicA20deletionintheSezarysyndrome-derivedcelllineSeAxwereidentified.
Furthermore,A20inhibitionactivatestheNF-κBpathway,therebyincreas-ingtheproliferationofnormalT-cells[17].
Interestingly,werecentlyfoundthattherearerareA20mutationsandpolymorphismsinT-ALL[25].
Therefore,itisofinteresttoanalyzetheexpressioncharacteristicsofA20anditsregulatingfactors,includingupstreamcomponentsoftheCBMcomplex,whichincludesCARMA1,BCL10,andMALT1[24,26-28],whichisexpectedtoprovidenewinsightintheabnormalmolecularregulationonT-cellactivation.
Inthisstudy,wecharacterizedthegeneexpressionpatternofA20,aswellasthegeneexpressionlevelsofitsupregulatingfactorsCARMA1-BCL10-MALT1anditstargetfactorNF-κBinT-ALL.
MethodsSamplesThesamplesusedinthisstudywerederivedfrom21newlydiagnosed,untreatedpatientswithT-ALL,includ-ing17malesand4females(4to66yearsold;medianage:23.
5years).
Sixteenhealthyindividualsincluding10malesand6females(17to45yearsold;medianage:26years)servedascontrols.
Peripheralbloodmono-nuclearcells(PBMCs)wereisolatedfromheparinizedvenousbloodbyFicoll-Paquegradientcentrifugation.
RNAextractionandcDNAsynthesisfromPBMCswereperformedaccordingtothemanufacturer'sinstructions.
Allhumanperipheralbloodsampleswereobtainedwithconsentfromthehumansubjects.
AllprocedureswereconductedaccordingtotheguidelinesoftheMedicalEthicsCommitteeoftheHealthBureauofGuangdongProvinceinChina,andethicalapprovalwasobtainedfromtheEthicsCommitteeoftheMedicalSchoolofJinanUniversity.
Quantitativereal-timeRT-PCR(qRT-PCR)ThesequencesoftheprimersusedforCARMA1,BCL-10,MALT1,A20,andNF-κBgeneamplificationarelistedinTable1.
TheexpressionleveloftheCARMA1,BCL-10,MALT1,A20,NF-κB,andβ2-microglobulin(β2M)geneswasdeterminedbySYBRGreenIreal-timePCRasprevi-ouslydescribed[4,25,29,30].
Therelativeamountsofthegenesofinterestandtheβ2Mreferencegeneweremea-suredintwoindependentassays.
Thespecific,amplifiedPCRproductswereanalyzedbymeltingcurveanalysis.
Thedataarepresentedastherelativeexpressionofthegenesofinterestcomparedwiththeinternalcontrolgeneasdeterminedbythe2(-ΔCT)method[4,28-30].
StatisticalanalysisTwoindependent-samplesMann-WhitneyUtestswereperformedtocomparethemedianexpressionlevelofeachgenebetweenpatientswithT-ALLandcontrolMaetal.
EuropeanJournalofMedicalResearch2014,19:62Page2of6http://www.
eurjmedres.
com/content/19/1/62individuals.
Spearmancorrelationandlinearregressionanalyseswereusedtodeterminetheassociationbe-tweendifferentgenesindifferentgroups.
AP<0.
05wasconsideredstatisticallysignificant[29,30].
ResultsanddiscussionDespitesignificantimprovementinourunderstandingofT-ALLbiologyandpathogenesis,knowledgeoftheon-cogenicsignalingpathwaysinvolvedinT-ALLremainslimited.
ConstitutiveaberrantactivationoftheNF-κBsignalingpathwayhasbeendetectedinvariouslymphoidmalignancies,anditplaysakeyroleinthedevelopmentofthesetumors.
A20isacentralregulatorinvolvedinthenegativefeedbackregulationofmultipleNF-κB-activatingsignalingcascades[16,18,31].
Recently,numer-ousstudiesshowedthatA20isinactivatedbydeletionsand/ormutationsinseverallymphomasubtypes,includ-ingT-celllymphomas[16-22],andA20inhibitionresultsinconstitutiveNF-κBactivationintumorcells.
ThesedataindicatethatA20inactivationmightplayaroleinmalig-nantT-cells.
Bi-andmonoallelicA20deletionsinahighproportionofSezarysyndromepatientswereidentified[16];however,mutationsandpolymorphismsinA20rarelyoccurinT-ALL[24].
Thus,itisofinteresttocharacterizetheA20expressionpatterninT-ALLscontaininganA20deletion.
Inthisstudy,weexaminedtheA20expressionlevelandfoundsignificantlylowerA20expressioninT-ALLpatients(median:4.
853)comparedwithhealthyindividuals(median:8.
748;P=0.
017)(Figure1A).
Thus,wehypothesizedthatA20downregulationmaybeduetoabnormalupstreamregulation.
Antigenreceptor-mediatedNF-κBactivationinlym-phocytesreliesontheformationofalargemulti-proteincomplexcontainingCARMA1,BCL10,andMALT1(CBM).
MALT1hasproteolyticactivityandcontrolsT-cellactivationbyregulatingNF-κBpathways[14,31],anditmediatesrapidproteolyticcleavageandA20inactivation[23].
StudiesinMALT1-deficientmicehavedemonstratedanessentialroleforMALT1inTCR-andB-cellreceptor-mediatedfunctions[15,28].
TheCARMA1-BCL10-MALT1pathwayispathologicallyalteredinseverallymphomasubtypes[32],includingactivatedB-cell-likediffuselargeB-celllymphoma(ABC-DLBCL)[33].
TheCARMA1-BCL10-MALT1pathwayalsoplaysacentralroleinTCRsignalingthatresultsinT-cellactivationandproliferation[24,26-28,34].
Inthisstudy,weattemptedtocharacterizedalterationsintheCBMgenesinT-ALL.
WeexaminedtheexpressionlevelsoftheCARMA1,BCL10,andMALT1genes,andsignificantlyincreasedexpressionlevelsofCARMA1(median:2.
916;P=0.
034),BCL10(median:0.
285;P=0.
033),andMALT1(median:1.
201;P=0.
010)werefoundinT-ALLpatientscomparedwithhealthyindividuals(median:1.
379,0.
169,and0.
677,re-spectively)(Figure1B–D).
HighexpressionoftheCBMgenesindicatessignificantlyhighleukemicT-cellactiva-tion,andhighMALT1expressionmightmediateA20downregulation,whichwasfoundinthesameT-ALLsamples.
ThisfindingmayalsopartiallyexplainthelowerexpressionlevelofA20inT-ALL.
BecauseCBMmediatesTCR-inducedNF-κBduringT-cellactivation,wefurtheranalyzedtheexpressionlevelofNF-κB,andasexpected,NF-κBoverexpression(median:0.
714)wasfoundinT-ALLpatientscomparedwithhealthycon-trols(median:0.
335;P=0.
001)(Figure1E).
Overall,weshowthattheabnormalexpressionofCBMandA20inT-ALLcellsmayberelatedtotheabnormalprolifera-tionofmalignantT-cells.
ThisresultisconsistentwiththefindingthatA20isalsoaputativetumorsuppressorinT-cellmalignanciessuchasSézarysyndrome.
Incon-trast,suchabnormalexpressioncharacteristicsmaybeconsideredasbiomarkersortargetfactorsinT-ALL.
OverexpressionofCARMA1wasreportedinangio-immunoblasticT-celllymphomaandperipheralT-celllymphoma,anditwaslinkedtopoorprognosisinare-portbyFujiwaraetal.
[35].
Additionally,inagenomeprofileanalysisofaggressiveadultT-cellleukemia/lymph-oma,CARMA1wasfoundtobeapotential7p22amplifi-cationtargetgeneinthelymphomabutnotacutesubtype.
Thisfindingsuggeststhattheacuteandlymphomasub-typesaregenomicallydistinct;thus,theymaydeveloptu-morsviadistinctgeneticpathways[7].
However,therearefewreportsofCBMmolecularaberrationsordysfunctioninT-ALL[4].
Inthisstudy,wefoundthatalloftheCBMgeneswereupregulated,resultinginthedownregulationofA20andupregulationofNF-κB,whichmaybeacom-moncharacteristicofabnormalproliferationandactiva-tioninT-cellmalignancies.
Therefore,itissuggestedthatsuchoverexpressedgenesmaybeconsideredpotentiallyattractivetargetsforthedevelopmentofT-ALLtherapeu-tics.
ItiswellknownthatNF-κBisatargetformultiplemyelomatherapyviaproteasomeinhibitorssuchasTable1Listofprimersusedforreal-timeRT-PCRPrimerSequenceCARMA1-f5′-ttgtgggagaatgtggagtgt-3′CARMA1-r5′-tgccccttggtatgtagaatg-3′BCL10-f5′-cccgctccgcctcctctcctt-3′BCL10-r5′-ggcgcttcttccgggtccg-3′MALT1-f5′-tcttggctggacagtttgtga-3′MALT1-r5′-gctctctgggatgtcgcaa-3′A20-f5′-ctgggaccatggcacaactc-3′A20-r5′-cggaaggttccatgggattc-3′NF-κB-f5′-ccacaagacagaagctgaag-3′NF-κB-r5′-agatactatctgtaagtgaacc-3′β2M-f5′-tacactgaattcacccccac-3′β2M-r5′-catccaatccaaatgcggca-3′Maetal.
EuropeanJournalofMedicalResearch2014,19:62Page3of6http://www.
eurjmedres.
com/content/19/1/62bortezomib[36],whichwasalsorecentlyusedincom-binedtherapyforT-cellmalignancies[37,38].
Moreover,twokindsofsmallmoleculeinhibitorforMALT1havebeenreportedrecently.
Oneofthemisthephenothiazinederivativemepazine,whichhasbeenshowntohaveprom-isinganticancerpropertiesinsubtypesofB-celllymphomaandcouldalsobeusedinthetreatmentoflymphocyte-mediatedautoimmunepathologiessuchasmultiplescler-osis[39].
TheotheroneisMI-2whichbindsdirectlytoMALT1andirreversiblysuppressesproteasefunction,anddisplaysselectiveactivityagainstABC-DLBCLcelllinesinvitroandxenotransplantedABC-DLBCLtumorsinvivo.
Itwouldbeworthytoinvestigatetheanti-T-ALLeffectofsuchMalt1inhibitors[40].
Wefurtheranalyzedassociationsbetweentheexpres-sionpatternsoftheCBM,A20,andNF-κBgenes.
A20isgenerallycleavedbyMALT1;thus,theexpressionlevelofMALT1shouldbenegativelycorrelatedwiththeA20andMALT1expressionpattern[41].
Wefoundanega-tivecorrelationbetweentheMALT1andA20expressionlevels(rs=–0.
806,P=<0.
0001)inthehealthyindividual(Figure2A)andT-ALLpatientgroups(rs=–0.
450,P=0.
041;Figure2B)asexpected.
AnegativecorrelationwasfoundbetweentheA20andNF-κBexpressionlevels(rs=–0.
847,P<0.
0001;Figure2C)inhealthyindivid-uals,asexpected,whiletherewasnosignificantcorrel-ationbetweentheA20andNF-κBexpressionlevelsinT-ALLpatients(rs=0.
0208,P=0.
929;Figure2D).
More-over,thenegativecorrelationwaslost,andwhetherthisisduetoabnormalCMBregulationremainsanopenquestion.
ApositivecorrelationbetweentheMALT1andNF-κBexpressionlevelwasalsofoundinhealthycontrols(rs=0.
641,P=0.
001;Figure2E),whiletherewasnosignificanceinthecorrelationbetweengenesintheT-ALLgroup(rs=0.
193,P=0.
402;Figure2F).
More-over,wefoundasignificantpositivecorrelationbetweenthegeneexpressionlevelsofCARMA1andBCL10inhealthyindividuals(rs=0.
513,P=0.
042;Figure2G)andT-ALLpatients(rs=0.
572,P=0.
007;Figure2H).
Overall,thisresultindicatesthatMALT1,A20,andNF-κBlosetheirnormalexpressionpatternatthemolecularlevel,andtheirmannerofregulationinT-ALLmaybemorecomplex.
Inourpreviousstudies,wefoundtwoT-ALLpatientswithtwomalignantVδ1andVδ2T-cellcloneswhohadpooroutcome,andhighexpressionoftheNotch1andCARMA-BCL10-MALT1-A20-NF-κBpathwaygenesinthisbiclonalT-ALLpatientgroupcomparedwithamono-malignantVαT-cellclonewasfound[4].
BasedFigure2Correlationanalysisoftheexpressionlevelsof(A)MALT1andA20inhealthyindividuals(HI),(B)MALT1andA20inT-ALL,(C)A20andNF-κBinHI,(D)A20andNF-κBinT-ALL,(E)MALT1andNF-κBinHI,(F)MALT1andNF-κBinT-ALL,(G)CARMA1andBCL10inHI,and(H)CARMA1andBCL10inT-ALL.
Figure1Theexpressionlevelsofthe(A)A20,(B)CARMA1,(C)BCL10,(D)MALT1,and(E)NF-ΚBgenesinhealthyindividualsandpatientswithT-ALL.
Maetal.
EuropeanJournalofMedicalResearch2014,19:62Page4of6http://www.
eurjmedres.
com/content/19/1/62onourdata,itisworthfurtherinvestigatingwhetherthedifferentexpressionpatternsoftheCARMA-BCL10-MALT1-A20-NF-κBpathwaygenesmaybeabiomarkerforagenomically-distinctsubtypeofT-ALLoraprog-nosticbiomarkerforT-ALL.
IncreasingnewgeneticmarkersforALLhavebeenfoundtohaveprognosticimpact[42].
ConclusionsWefirstcharacterizedtheexpressionpatternoftheCARMA-BCL10-MALT1-A20-NF-κBpathwaygenesandfoundthatoverexpressionofCBMgenesinT-ALLmaycauseconstitutivecleavageandinactivationofA20toenhanceNF-κBsignaling,contributingtothepathogen-esisofT-ALL.
Thus,thispathwaymaybeconsideredapotentiallyattractivetargetforthedevelopmentofT-ALLtherapeutics.
However,thisfindingisbasedonlyonresultsfromalimitedcaseanalysisandfurtherresearchinvolvingmoresamplesisneededtodeterminerepre-sentativeresults.
Moreover,thechangeofproteinlevelsofthispathwayareneededtoconfirmthis,especiallyfortargettherapeuticstrategyinT-ALL.
AbbreviationsABC-DLBCL:ActivatedB-cell-likediffuselargeB-celllymphoma;A20:Tumornecrosisfactoralpha-inducedprotein3(TNFAIP3);Bcl-10:B-celllymphoma10;BCL11B:B-cellchroniclymphocyticleukemia/lymphoma11B);β2M:β2-microglobulin;CARMA1:Caspase-recruitmentdomain(CARD)containingmembrane-associatedguanylatekinaseprotein1(CARD11);CBM:CARMA1,BCL10,andMALT1;MALT1:Mucosa-associated-lymphoid-tissuelymphoma-translocationgene1;NF-κB:NuclearfactorκB;PBMCs:Peripheralbloodmononuclearcells;qRT-PCR:Quantitativereal-timeRT-PCR;T-ALL:T-cellacutelymphoblasticleukemia;TCR:T-cellreceptor.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsYQLandXLWcontributedtotheconceptdevelopmentandstudydesign.
YM,LHZ,YX,ZYZ,XW,andFZperformedthereal-timePCR.
SHCandLJYperformedPBMCisolation,RNAextraction,andcDNAsynthesis.
GXLandXHwereresponsibleforthecollectionofclinicaldata.
YQL,XLW,SUH,YM,andLHZcoordinatedthestudyandhelpeddraftthemanuscript.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgmentsThisstudywassupportedbygrantsfromtheNationalNaturalScienceFoundationofChina(Nos.
91129720,81100384),theGuangdongScience&TechnologyProject(2012B050600023),ScienceandTechnologyInnovationKeyProjectofGuangdongHigherEducationInstitutes(kjcxzd1013),theMedicalScienceFoundationofGuangdongProvince(A2014371),andtheGuangdongprovincialundergraduatetrainingprogramforinnovationandentrepreneurship(1055912064).
Authordetails1InstituteofHematology,JinanUniversity,Guangzhou510632,China.
2DepartmentofMedicine,ImperialCollegeLondon,StMary'sCampus,LondonW21PG,UK.
3KeyLaboratoryforRegenerativeMedicineofMinistryofEducation,JinanUniversity,Guangzhou510632,China.
4DepartmentofHematology,GuangdongGeneralHospital(GuangdongAcademyofMedicalSciences),Guangzhou510080,People'sRepublicofChina.
5DepartmentofBiochemistryandMolecularBiology,CollegeofMedicine,UniversityofFlorida,Gainesville,FL32610-3633,USA.
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doi:10.
1186/s40001-014-0062-8Citethisarticleas:Maetal.
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