96|NATURE|VOL553|4jANUARy2018LETTERdoi:10.1038/nature25167Senescence-associatedreprogrammingpromotescancerstemnessMajaMilanovic1,DorothyN.y.Fan1,2,3,4,DimitriBelenki1,j.HenryM.Däbritz1,ZhenZhao5,yongyu6,janR.Dörr1,LoraDimitrova7,DidoLenze7,InesA.MonteiroBarbosa8,MarcoA.Mendoza-Parra9,TamaraKanashova6,MarlenMetzner1,KatharinaPardon1,MauriceReimann1,AndreasTrumpp2,3,4,10,BerndDörken1,2,4,6,11,johannesZuber8,HinrichGronemeyer9,MichaelHummel2,4,7,11,GunnarDittmar6,12,SoyoungLee1,2,4,6&ClemensA.Schmitt1,2,4,6,11Cellularsenescenceisastress-responsivecell-cyclearrestprogramthatterminatesthefurtherexpansionof(pre-)malignantcells1,2.Keysignallingcomponentsofthesenescencemachinery,suchasp16INK4a,p21CIP1andp53,aswellastrimethylationoflysine9athistoneH3(H3K9me3),alsooperateascriticalregulatorsofstem-cellfunctions(whicharecollectivelytermed‘stemness’)3.Incancercells,againofstemnessmayhaveprofoundimplicationsfortumouraggressivenessandclinicaloutcome.Hereweinvestigatedwhetherchemotherapy-inducedsenescencecouldchangestem-cell-relatedpropertiesofmalignantcells.Geneexpressionandfunctionalanalysescomparingsenescentandnon-senescentB-celllymphomasfromEμ-Myctransgenicmicerevealedsubstantialupregulationofanadulttissuestem-cellsignature,activatedWntsignalling,anddistinctstem-cellmarkersinsenescence.UsinggeneticallyswitchablemodelsofsenescencetargetingH3K9me3orp53tomimicspontaneousescapefromthearrestedcondition,wefoundthatcellsreleasedfromsenescencere-enteredthecellcyclewithstronglyenhancedandWnt-dependentclonogenicgrowthpotentialcomparedtovirtuallyidenticalpopulationsthathadbeenequallyexposedtochemotherapybuthadneverbeensenescent.Invivo,thesepreviouslysenescentcellspresentedwithamuchhighertumourinitiationpotential.Notably,thetemporaryenforcementofsenescenceinp53-regulatablemodelsofacutelymphoblasticleukaemiaandacutemyeloidleukaemiawasfoundtoreprogramnon-stembulkleukaemiacellsintoself-renewing,leukaemia-initiatingstemcells.Ourdata,whicharefurthersupportedbyconsistentresultsinhumanc...
