hnRNPswww.bu622.com

RESEARCHOpenAccessProteomicprofileofpre-B2lymphoblastsfromchildrenwithacutelymphoblasticleukemia(ALL)inrelationwiththetranslocation(12;21)OdileCosta1*,PascaleSchneider1,2*,LaurentCoquet3,4,PhilippeChan3,DominiquePenther5,ElisabethLegrand1,ThierryJouenne3,4,MarcVasse1andJean-PierreVannier1,2AbstractBackground:Untilnow,themajorprognosticfactorsforpediatricacutelymphoblasticleukemia(ALL),age,whitebloodcellcountandchromosomalalterationsareinitiallytakenintoaccountfortheriskstratificationofpatients.
InthelightofproteinmarkerstudiestoclassifysubtypesofAcuteMyeloblasticLeukemiaefficiently,wehavecomparedthelymphoblastesproteomeinChildhoodALLinaccordancewiththepresenceoft(12;21),indicatorofgoodprognosis,usually.
Methods:Proteinexpressioninpre-B2lymphoblasticcells,collectedfromresidualbonemarrowcellsafterdiagnosticprocedures,wasanalyzedusingtwodimensionalgelelectrophoresisprotocol.
Proteinspotswhoseaveragenormalizedvolumeswerestatisticallydifferentinthetwopatientsgroups(n=13;studentttestp48)(seeOnlineAdditionalfile1:FigureS3)wereofgreatinterestintermsofleukemogenesissincein-volvedinmechanismsrelatedtoeitherthecellcycleregu-lation,orapoptosis,orenergeticmetabolism(i.
e.
,43%,29%or28%ofthem,respectively)(Figure2B).
PrincipalCostaetal.
ClinicalProteomics2014,11:31Page2of12http://www.
clinicalproteomicsjournal.
com/content/11/1/31Table1Clinicalandbiologicalstatusofchildhoodpre-B2ALLpatientsGroupofALLpatientsPatientsIDAgeatdiagnosis(Months)Peripheralbloodlymphocytes(Giga/L)KaryotypeFusiontranscriptsOutcomeWitht(12;21)BACYO2448,7t(12;21)ETV6/RUNX1CR1GUEKE11842,2t(12;21)ETV6/RUNX1CR1LECRO765,4t(12;21)ETV6/RUNX1CR1MARLE42166t(12;21)ETV6/RUNX1CR1PELAD5020t(12;21)ETV6/RUNX1Dead*RIFEM76216t(12;21)ETV6/RUNX1CR1OtherkaryotypeabnormalitiesBOILE182,8dic(9;20)NACR1CREBA18011,6mono21NACR1DESNA1315,5rear9pNACR1JUGEL348,5HyperploidyNACR1LEMAL4856t(9;22)BCL/ABL1CR1MORLU171171t(9;22)BCL/ABL1Dead*ROSLO576,1HyperploidyNACR1TheboldnumbersindicatesvalueshigherthethresholdofFRALLE2000protocol.
CR1=Firstcompleteremission;dic=dicentric;ID=Identification;mono=monosomy;NA=Notapplicable;rear=Rearrangement.
*=DirectlyrelatedtotherecurrenceofALL.
Figure1Differentialexpressionofproteinsinbonemarrowlymphoblasticcellsfromchildhoodpre-BALL.
–A–Down:Two-DEgelimageoflymphoblasticcellsproteinsissuingfrombonemarrow.
NumbersrefertothetopelevenproteinswhichhavebeencharacterizedandlistedinTable1b.
Up:Magnificationviewofinterestingzone–B–3Dmontageofthethreetopdifferentiallyexpressedspotproteins(i.
e.
,2-DEBatch2768,3185and4083onrank1,2and3,respectively).
Only2individualspotimagesineachgroup(1and2=Pre-B2ALLwitht(12;21),1′and2′=Pre-B2ALLwithotherkaryotypeabnormalities)areshown.
Costaetal.
ClinicalProteomics2014,11:31Page3of12http://www.
clinicalproteomicsjournal.
com/content/11/1/31Table2Theclassificationofdifferentiallyexpressedproteinsinpre-B2lymphoblasticcellsfromchildrenwithALLSpots:statisticrank(2-DEbatch)Proteinnames[Homosapiens]NCBIanduniprotIDnumbersFoldchanges/ALLt(12;21)versusothers(averagenormalizedvolume+/SD)105GroupwiththeupperaveragevolumeStudent-ttestPower(afterqvalue)1(2768)CNN2gi/49456619/Q994391.
9/(38.
59+/8.
1vs20.
76+/4)Pre-B2,t(12;21)p≤0.
0010.
9982(3185)CDSαgi/32307132/Q9Y697-12.
2/(9.
5+/3.
8vs20.
98+/5.
2)OtherPre-B2p≤0.
0010.
9853(4083)PITPβgi/6912594/P487392/(12.
8+/3.
1vs6.
28+/2.
21)Pre-B2,t(12;21)p≤0.
0010.
9834(2457)hnRNP-E1gi/460771/Q153651.
4/(29.
87+/4.
69vs41.
57+/4.
88)OtherPre-B2p≤0.
0050.
976BUB3αgi/4757880/O436845(4069)PDH-E1gi/149242791/P13804-11.
5/(15.
16+/4.
33vs23.
29+/3.
12)OtherPre-B2p≤0.
0050.
9556(2090)MAT2βi1gi/11034825/Q9NZL91.
5/(21.
94+/3.
89vs15.
06+/2.
91)Pre-B2,t(12;21)p≤0.
0050.
9157(2800)PSMB2gi/4506195/B7Z4781.
7/(9.
48+/2.
49vs5.
69+/1.
63)Pre-B2,t(12;21)p≤0.
010.
8788(4081)CECR5gi/14861834/Q9BXW71.
3/(28.
51+/4.
48vs37.
3+/4.
81)OtherPre-B2p≤0.
010.
867BUB3αgi/4757880/O436849(3121)CK2αgi/4503095/P684001.
5/(13.
55+/2.
36vs20.
31+/4.
9)OtherPre-B2p≤0.
010.
864SEPT9i3gi/668381/Q9UHD8-310(2056)HnRNPA2gi/4504447/P22626-22/(18.
28+/6.
56vs9.
26+/4.
77)Pre-B2,t(12;21)p≤0.
010.
85411(3120)IVADgi/3212539/P264401.
5/(14.
98+/3.
44vs22.
64+/5.
34)OtherPreB2p≤0.
010.
835FBAgi/312137/P05062PSMB6gi/1526426/P6233312(2656)OTUB1gi/6841176/Q96FW11.
8/(58.
54+/19.
8vs(32.
01+/14.
53)Pre-B2,t(12;21)p≤0.
050.
787Two-dimensionalgelelectrophoresis(2-DE)BatchesarelocatedFigure1A(incaseofthetopeleven)andAdditionalfile1:FigureS2(forthefollowing15th).
Incolumn'proteinnames,R1,R2andR3aretheMascotrankbasedonthewholeionicscoresdetected(upperorequalto48).
Poweranalysisisperformedindependentlyforeachspot,takingintoconsiderationthesamplesizeandvarianceexpressionvalue(ProgenesisSameSpotsV4).
CNN2=calponin-2;CDSα=cysteinedesulfurase,mitochondrialisoforma;PITPβ=phosphatidyl-inositoltransferproteinbetaisoform;BUB3a=mitoticcheckpointproteinBUB3isoforma;PDHE1=chainA,pyruvatedehydrogenaseE1S264eVariant;MAT2β=methionineadenosyltransferase2,subunitbeta,isoform1;PSMB2=proteasomesubunitbetatype-2,isoform1;CECR5=cateyesyndromecriticalregionprotein5isoform2;CK2α=caseinkinaseIIsubunitalphaisoforma;SEPT9_i3=MLLseptin-likefusionproteinMSF-B;hnRNPA2=heterogeneousnuclearribonucleo-proteinsA2;IVAD=ChainA,isovaleryl-Coadehydrogenase;FBA=fructosebisphosphatealdolase;PSMB6=proteasomesubunit6(p42);OTUB1=deubiquitinatingenzymeOTUB1.
Costaetal.
ClinicalProteomics2014,11:31Page4of12http://www.
clinicalproteomicsjournal.
com/content/11/1/31componentsanalysis(PCA)(seePatients,materialsandmethods)indicatedthattheamountofallthe26spotsofinterest,whengatheredtogether,coulddiscriminate2groupsofpatient,correlatingwiththepresenceorabsenceoft(12;21)(Figure4A,B).
Amongtheproteinsinvolvedincellcycleregula-tion,arethecalponin-2(CNN2)andmethionineade-nosyltransferase2beta(MAT2β)variant1,whicharehighlyexpressedinALLwitht(12;21),usuallyassociatedtogoodprognosis(p0.
01andp≤0.
05(n=15);B/Spotsdifferentiallyexpressedwithp≤0.
01(n=11).
NamesclosetodotesareidentificationbadgeofpatientslistedinTable1.
Costaetal.
ClinicalProteomics2014,11:31Page6of12http://www.
clinicalproteomicsjournal.
com/content/11/1/31Table3ConcludingremarksandfuturedirectionsExpressionobservedint(12;21)ALLsMajorexpectedcellulareffectsCommentsFuturedirectionsOverexpressionofCNN2MediatescellulargrowtharrestInfavorofgoodprognosisassociatedtot(12;21)IsCNN2amarkerofgoodprognosisIthastobeconfirmedwithalargestgroupofpatientsOverexpressionofMAT-2βFavorsthecellproliferationwithanti-apoptoticeffectWouldbeamarkerofcanceraggressivenessWouldbeexploreasatargetofchemotherapyOverexpressionofhnRNPA2FavorsthecellproliferationWouldbeamarkerofcanceraggressivenessWouldbeexploreasatargetofchemotherapyOverexpressionofPITPβSlowdownthecellproliferationIsitamarkerofgoodprognosisExplorationofthebalancePITPα/βUnderexpressionofBUB3AvoidslippageofmitosisOverexpressioninnont(12;21)couldleadtohypo/hyperpolyploidcellsMitosesanalysisUnderexpressionofhnRNPE2FavorsapoptosisInfavorofgoodprognosisassociatedtot(12;21)ExplorationofthebalancebetweenhnRNPE2,PSMB2andPSMB6and/orcheckuptheapoptosispathwaysOverexpressionofPSMB2FavorsapoptosisUnderexpressionofPSMB6HindersapoptosisInfavorofleukogenesisUnderexpressionofCK2αSlowdowntheproliferationbyapoptoticeffectInfavorofgoodprognosisassociatedtot(12;21)BothexpressionsincombinationwithIkaros(Ikzf1)phosphorylationanddegradationoughttobeclarifiedpreciselyOverexpressionofHSPC263(OTUB1)FavorsdeubiquitinationDoesitpreventIkaros(Ikzf1)degradationUnderexpressionofmetabolismpathwayproteins(i.
e.
,CDSα;CECR5;PDH;IVAD;IDH;Electrontransferflavoprotein)SignthelevelofenergeticconsumptionInfavorofgoodprognosisassociatedtot(12;21)Checkuplymphoblastsmetabolismpathway:HighamountwouldbeinaccordwithcanceraggressivenessCostaetal.
ClinicalProteomics2014,11:31Page7of12http://www.
clinicalproteomicsjournal.
com/content/11/1/31theregulatorysubunitoftheisozyme[15,17].
Whenex-pressionofMAT2βissuccessfullysilenced,excessiveapoptosisandgrowthslowdownisobservedinJurkatleukemicTcell[17,18].
RecentlyMAT2βv1(herechar-acterized),hasbeenidentifiedasananti-apoptoticcom-ponentthroughSirtuin1signaling[19].
Therefore,theoverexpressionofMAT2βint(12;21)ALLscannotbeconsideredasagoodprognosticfactor.
ItseemstohavetheoppositeeffectoncellproliferationwhencomparedtoCNN2.
MAT-2βhastobeevaluatedasapossibletargettoimproveprognosisinthet(12;21)ALLs(Table3).
HnRNPA2functionsastelomericcappingfactorprotect-ingtelomericDNAinvivoagainstnucleasedigestionbyrecruitingtheessentialRNAsubunit(hTR)tothetelomere[20].
RNAi,reductionofhnRNPA1andhnRNPA2signifi-cantlyreducedtheproliferationrateofColo16cells,sug-gestingthatthesehnRNPmembersmaybeclassifiedasoncogenes[21].
HnRNPA2isfoundoverexpressedint(12,21)ALLsandthuswouldcontributetofavorthepre-B2prolif-erationandwouldbeamarkerofleukemogenesis(Table3).
Thethreelastproteinsincludedinthisgroup(i.
e.
hnRNP-E1,BUB3αandSEPT9_i4)areunderexpressedint(12;21)ALLs.
HnRNPE1isamemberoftheRNAbindingproteinfam-ilywhichincludesimportantmitoticregulatorsandeffec-tors,havingmultiplefunctionsinhematopoieticcells.
Itisinvolvedincontrollingstemcellproliferationanddifferen-tiation[21,22].
Particularly,actingas"chaperone"moleculeontheRNA,hnRNPsE1functionsascrucialmodulatorofmRNAstability,andtranslationinhematopoieticcelldifferentiation[23].
Itstimulatesthetranslationofc-mycandBag-1,havingananti-apoptoticeffectoncancercells[21,24].
TheaccumulationofhnRNPE1inlymphoblastescouldinduceananti-apoptoticeffect,worseningthedisease.
TheunderexpressionofhnRNPE2observedint(12;21)ALLswouldcontributetoapoptosisintheseleukemiccells(Table3).
TheBUB3αisoneofthecomponentsofthespindleas-semblycheckpoint(SAC)whichinteractswithBUB1andleadstodelaythecellcycleprogression[25].
However,inconditionswheretheSACiskeptactive,somecellsescapefrommitosis,resultinginpolyploidcells[25].
Itsoverex-pressioninnont(12;21)ALLscouldcontributetotheslip-pageofmitosistowardahypo/polyploidcells(Table3).
SEPT9_i4isanisoformoftheGTPbindingseptinfamily,involvedincytokinesis.
OverexpressionoftheshortisoformSEPT9_i4disturbsseptininteractionsandcellularmotilitywhichcanberelatedtoneoplasicasso-ciatedphenotypes[26].
SEPT9_i4overexpressingcellshaveenhancedsurvivalinthepresenceofclinicallyrele-vantmicrotubuleactingdrugs.
Itsoverexpressioninseveralcancersmaybeclinicallyrelevantwithacontri-butionofdrugresistanceformsofcancer[27].
Thisi4variantistheCOOHterminalsequenceofalltheisoformes[28].
Therebyitmaybedifficulttoreachitasaspecifictarget.
ByintroducingmutationsthatpreventSEPT9self-associationattheN-andC-termini,ithasbeenshownthatseptinfilamentdisruptioncausesde-fectsinthelatestagesofcelldivisionbeforeabscission,similartotheseobserveduponSEPT9depletion[28].
ProteinsinvolvedinapoptosisAmongproteinswhichareprincipallyimplicatedinapop-toticpathwaysandmayhaveaprognosticvalue(i.
e.
,PITPβ,CK2α,andPSMB2,PSMB6),phosphatidylinositoltransferproteinsbeta(PITPβ)andCK2αhaveanimpactonPl3Kpathway.
PITPβwashighlyexpressedinthegroupoft(12;21)ALLs.
Physiologically,PITPβispoorlyexpressedandfa-vorstheactivationofagolgianPI3K[29].
PITPβaccu-mulation,bymodifyingthebalancePITPα/β,inducesadecreaseofproliferationandanincreaseofapoptosis[30].
TheexplorationofthebalancePITPα/βinALLsmaybeausefulbiologicalmarker.
Onthecontrary,CK2αwasunderexpressedint(12;21)ALLs.
CK2αdisturbsthePI3Kpathwaybyphos-phorylatingPTENandAKT,therebyfavoringcellprolif-erationbyananti-apoptoticeffect[7,31].
TheoverexpressionofCK2αhasbeenshowntoincreasethedeg-radationofIkarosprotein(i.
e.
,atumorsuppressorinALL)viatheubiquitinpathway[3,32,33].
Interestinglyinthet(12,21)ALLs,notonlyCK2αisunderexpressedbutOTUB1,adeubiquitinatingenzyme,isfoundslightlyoverexpressed(seeTable2,rank12)[34].
OTUB1hydrolasecanspecificallyremove'Lys-48"-linkedconju-gatedubiquitinfromproteinsandplaysanimportantregulatoryroleatthelevelofproteinturnoverbypre-ventingdegradation.
Ithasrecentlybeenidentifiedasanovelp53regulator[35].
AlltogetherthiscouldresultinanpreservationofIkarosfunctionsandwouldcontributetothegoodprognosticclaimedfort(12;21)ALLs.
Thetwootherproteinsimplicatedinapoptosis(i.
e.
,PSMB2andPSMB6)areconstitutiveoftheproteasome.
Theproteasomeisresponsibleforthedegradationofintracellularproteinsinvolvedincellcyclecontrolandregulationofapoptosis,includingthetumorsuppressorproteinp53andspecificcyclindependentkinases[36].
AtthistimewecannotexplainwhyPSMB2ispredominantint(12;21)ALLs,whilePSMB6isweaklyexpressed.
Newtherapiesagainsttumorgrowthanddevelopmenthaveananti-ubiquitin-proteasomepathwayeffect[36].
Twopathwaysinwhichmostoftheseproteins(i.
e.
,in-volvedinapoptosisandalsoBUB3)werepointedoutwithProteinCenterSoftware(ThermoScientificProteinCenterSoftware).
Thefirstone(Rawp-value,p0.
01andp≤0.
05)arenumbered.
NumberscorrespondtoproteinspotslistedinTable2.
FigureS3.
Mascotresearchresultsforthefirstelevenspotproteinsorderedbystatisticrank(ProgenesisSameSpotsV4software–seeAdditionalfile1:TableS1).
Foreachidentifiedtrypsicpeptide,individualionsscoresupto48indicateidentityorextensivehomology(p<0.
05).
Matchedpeptidesareshowninboldred.
Abbreviations2-DE:Two-dimensionalpolyacrylamidegelelectrophoresis;ALL:Acutelymphoblasticleukemia;CNN2:h2-calponin;MAT2Bβ:Methionineadenosyltransferase2β;hnRNP-E1:Heterogeneousnuclearribonucleoprotein-E1;BUB3α:MitoticcheckpointproteinBUB3isoforma;MSF-B:SEPT9_i4,MLLseptin-likefusionprotein;PITPβ:Phosphatidylinositoltransferproteinsbeta;CK2α:Caseinkinase2alpha;PSMB6:Proteasomesubunitsbeta2,PSMB2,proteasomesubunitsbeta6(p42);CDSα:Cysteindesulfurasemitochondrialisoformα;PDH:Pyruvatedehydrogenase;IVAD:IsovalerylCoAdehydrogenase.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
OnlineSupplementaryinformationsareavailableatwww.
haematologica.
org.
Costaetal.
ClinicalProteomics2014,11:31Page10of12http://www.
clinicalproteomicsjournal.
com/content/11/1/31Authors'contributionsOC,PhD,MCU,performedanddesignedresearch,analyzeddata,andwrotethemanuscript;PS,MD,PUPH,ispediatrichematologistandwrotethemanuscript;EL,Technician,keepgrowingcelllines,DP,MD,performedcytogeneticanalysis,LC,PhD,RI,andPC,PhD,RI,performedmassspectrometryresearch,TJ,PhD,PU,DirectorofPISSAROProteomicfacility;MV,PUPHandJ-PV,MD,PUPHcontributedvitalreagents.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgmentsTheauthorsthankFranoiseThouretforhertechnicalassistanceinleukemiacellspreparations.
Thisworkwassupportedbygrantsfrom:theLionsclubsfromNormandie(France),theFondationMartineMIDY(France)andtheAssociationLauretteFUGAIN,conventionALF/N°10-07(France).
Authordetails1LaboratoireMERCI,FacultédeMédecineetdePharmaciedeRouen,123boulevardGambetta,Rouen,Cedex76183,France.
2Serviced'Immuno-HématologieOnco-pédiatriqueduCHRUdeRouen,HpitalCharlesNicolle,Rouen76031,France.
3PISSAROProteomicfacility,(IRIB),U-Rouen,MontSaint-Aignan,France.
4CNRSUMR6270,TeamBiofilms,Résistance,InteractionsCellules-Surfaces,U-Rouen,MontSaint-Aignan,France.
5LaboratoiredeCytogénétique,CentreHenriBecquerel,Rouen76000,France.
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