104|NATURE|VOL547|6JULy2017LETTERdoi:10.1038/nature22993TracingtheoriginsofrelapseinacutemyeloidleukaemiatostemcellsLiranI.Shlush1,2,3*,AmandaMitchell1*,LawrenceHeisler4,SagiAbelson1,StanleyW.K.Ng1,AaronTrotman-Grant1,JessieJ.F.Medeiros1,AbilashaRao-Bhatia1,IvanaJaciw-Zurakowsky1,ReneMarke5,JessicaL.McLeod1,MonicaDoedens1,GaryBader6,7,VeroniqueVoisin7,ChangJiangXu7,JohnD.McPherson4,ThomasJ.Hudson4,6,8,JeanC.y.Wang1,9,10,MarkD.Minden1,8,9,10&JohnE.Dick1,6Inacutemyeloidleukaemia,long-termsurvivalispoorasmostpatientsrelapsedespiteachievingremission1.Historically,thefailureoftherapyhasbeenthoughttobeduetomutationsthatproducedrugresistance,possiblyarisingasaconsequenceofthemutagenicpropertiesofchemotherapydrugs2.However,otherlinesofevidencehavepointedtothepre-existenceofdrug-resistantcells3.Forexample,deepsequencingofpaireddiagnosisandrelapseacutemyeloidleukaemiasampleshasprovideddirectevidencethatrelapseinsomecasesisgeneratedfromminorgeneticsubclonespresentatdiagnosisthatsurvivechemotherapy3–5,suggestingthatresistantcellsaregeneratedbyevolutionaryprocessesbeforetreatment3andareselectedbytherapy6–8.Nevertheless,themechanismsoftherapyfailureandcapacityforleukaemicregenerationremainobscure,assequenceanalysisalonedoesnotprovideinsightintothecelltypesthatarefatedtodriverelapse.Althoughleukaemiastemcells9,10havebeenlinkedtorelapseowingtotheirdormancyandself-renewalproperties11–13,andleukaemiastemcellgeneexpressionsignaturesarehighlypredictiveoftherapyfailure14,15,experimentalstudieshavebeenprimarilycorrelative7andaroleforleukaemiastemcellsinacutemyeloidleukaemiarelapsehasnotbeendirectlyproved.Here,throughcombinedgeneticandfunctionalanalysisofpurifiedsubpopulationsandxenograftsfrompaireddiagnosis/relapsesamples,weidentifytherapy-resistantcellsalreadypresentatdiagnosisandtwomajorpatternsofrelapse.Insomecases,relapseoriginatedfromrareleukaemiastemcellswithahaematopoieticstem/progenitorcellphenotype,whileinotherinstancesrelapsedevelopedfromlargersubclonesofimmunophenotypica...
