ReviewSeriesLEUKEMICSTEMCELLSBiologyandrelevanceofhumanacutemyeloidleukemiastemcellsDanielThomasandRavindraMajetiDivisionofHematology,DepartmentofMedicine,CancerInstituteandInstituteforStemCellBiologyandRegenerativeMedicine,StanfordUniversitySchoolofMedicine,Stanford,CAEvidenceofhumanacutemyeloidleuke-miastemcells(AMLLSCs)wasfirstreportednearly2decadesagothroughtheidentificationofraresubpopulationsofengraftingcellsinxenotransplantationassays.TheseAMLLSCswereshowntoresideattheapexofacellularhierarchythatinitiatesandmaintainsthedisease,exhibitingpropertiesofself-renewal,cellcyclequiescence,andchemoresistance.ThiscancerstemcellmodeloffersanexplanationforchemotherapyresistanceanddiseaserelapseandimpliesthatapproachestotreatmentmusteradicateLSCsforcure.Morerecently,anumberofstudieshavebothrefinedandexpandedourunderstandingofLSCsandintrapatientheterogeneityinAMLusingimprovedxenotransplantmodels,genome-scaleanal-yses,andexperimentalmanipulationofprimarypatientcells.Here,wereviewthesestudieswithafocusontheimmunopheno-type,biologicalproperties,epigenetics,ge-netics,andclinicalassociationsofhumanAMLLSCsanddiscusscriticalquestionsthatneedtobeaddressedinfutureresearch.(Blood.2017;129(12):1577-1585)IntroductionAcutemyeloidleukemia(AML)isarapidlyprogressinghematopoieticmalignancy,characterizedbytheaccumulationofclonalmyeloidprogenitorcellsarrestedintheirabilitytodifferentiateintomaturebloodcellsthatisaccompaniedbymultilineagecytopenias.1Indeed,itisthelackofnormalcells,includingredbloodcells,platelets,andgranulocytes,thateventuallycontributestomorbidityinthisdisease.Whilereductionsinleukemicblastscanbeachievedinitiallywithcytarabineandanthracyclinechemotherapyinthemajorityofpatients,long-termoutcomeshavenotimprovedsignificantlyforover3decades,with5-yearoverallsurvivalratesforpatients,60yearsrangingfrom35%to40%andmedianoverallsurvivalof;1year.1,2ManysamplesfrompatientswithAMLshowevidenceofahierarchicalcellularorganization,withaminorfractionofself-renewingleukemiastemcells(LSCs)a...
