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1、PublishedOnlineFirstNovember21,2016;DOI:10.1158/0008-5472.CAN-16-1303CancerMolecularandCellularPathobiologyResearchMutationalLandscapeofPediatricAcuteLymphoblasticLeukemia1111Ling-WenDing,Qiao-YangSun,Kar-TongTan,WenwenChien,112,3AnandMayakondaThippeswamy,AllenEngJuhYeoh,No
2、rihikoKawamata,4111,31,5YasunobuNagata,Jin-FenXiao,Xin-YiLoh,De-ChenLin,ManojGarg,111114,6Yan-YiJiang,LiangXu,Su-LinLim,Li-ZhenLiu,VikasMadan,MasashiSanada,1137LuciaTorresFernandez,HemaPreethi,MichaelLill,HagopM.Kantarjian,78,9104StevenM.Kornblau,SatoruMiyano,Der-CherngLia
3、ng,SeishiOgawa,1111,2Lee-YungShih,HenryYang,andH.PhillipKoefflerAbstractCurrentstandardofcareforpatientswithpediatricacutelym-recurrentmutationalhotspotswereobservedinepigeneticregula-phoblasticleukemia(ALL)ismainlyeffective,withhighremissiontorsCREBBP(R1446C/H),WHSC1(E1099K
4、),andthetyrosineratesaftertreatment.However,thegeneticperturbationsthatgivekinaseFLT3(K663R,N676K).ThemutantWHSC1wasestablishedrisetothisdiseaseremainlargelyundefined,limitingtheabilitytoasagain-of-functiononcogene,whiletheepigeneticregulatoraddressresistanttumorsordevelople
5、sstoxictargetedtherapies.ARID1AandtranscriptionfactorCTCFwerefunctionallyidentifiedHere,wereporttheuseofnext-generationsequencingtointerro-aspotentialtumorsuppressors.Analysisof28diagnosis/relapsegatethegeneticandpathogenicmechanismsof240pediatricALLtriopatientsplus10relapse
6、casesrevealedfourevolutionarycaseswiththeirmatchedremissionsamples.Commonlymutatedpathsanduncoveredtheorderingofacquisitionofmutationsingenesfellintoseveralcategories,includingRAS/receptortyrosinethesepatients.Thisstudyprovidesadetailedmutationalportraitkinases,epigeneticre
7、gulators,transcriptionfactorsinvolvedinofpediatricALLandgivesinsightsintothemolecularpathogen-lineagecommitment,andthep53/cell-cyclepathway.Uniqueesisofthisdisease.CancerRes;77(2);390–400.Ó2016AACR.Introductiondeaths(1).UnlikeadultALL,mostpediatricALLpatientsrespondwelltoco
8、nventionalchemotherapy,andthe5-yearoverallsurvivalPediatricacutelymphoblasticleuke
