AmericanSocietyofHematology2021LStreetNW,Suite900,Washington,DC20036Phone:202-776-0544|Fax202-776-0545editorial@hematology.orgCircMYBL2,acircRNAfromMYBL2,RegulatesFLT3TranslationbyRecruitingPTBP1toPromoteFLT3-ITDAMLProgressionTrackingno:BLD-2019-000802R2Yu-MengSun(SunYat-senUniversity,)Wen-TaoWang(SunYat-senUniversity,)Zhan-ChengZeng(SunYat-senUniversity,)Tian-QiChen(SunYat-senUniversity,)CaiHan(SunYat-senUniversity,)QiPan(SunYat-senUniversity,China)WeiHuang(SunYat-senUniversity,)KeFang(SunYat-senUniversity,China)Lin-YuSun(SunYat-senUniversity,China)Yan-FeiZhou(SunYat-senUniversity,)Xue-QunLuo(SunYat-senUniversity,)ChengweiLuo(GuangdongProvincialPeople'sHospital,China)XinDu(GuangdongGeneralHospital,China)Yue-QinChen(SunYat-senUniversity,China)Abstract:Internaltandemduplication(ITD)mutationswithintheFMS-liketyrosinekinase-3(FLT3)occurinupto30%ofacutemyeloidleukemia(AML)patientsandconferaverypoorprognosis.TheoncogenicformofFLT3isanimportanttherapeutictarget,andinhibitorsspecificallytargetingFLT3kinasecaninducecompleteremission;however,relapseafterremissionhasbeenobservedduetoacquiredresistancewithsecondarymutationsinFLT3,highlightingtheneedfornewstrategiestotargetFLT3-ITDmutations.RecentstudieshavereportedthattheaberrantformationsofcircularRNAs(circRNAs)arebiologicaltumorigenesis-relevantmechanismsandpotentialtherapeutictargets.Herein,wediscoveredacircRNA,circMYBL2,derivedfromthecellcyclecheckpointgeneMYBL2.CircMYBL2ismorehighlyexpressedinAMLpatientswithFLT3-ITDmutationsthaninthosewithouttheFLT3-ITDmutation.WefoundthatcircMYBL2knockdownspecificallyinhibitsproliferationandpromotesthedifferentiationofFLT3-ITDAMLcellsinvitroandinvivo.Interestingly,wefoundthatcircMYBL2significantlyinfluencestheproteinlevelofmutantFLT3kinase,whichcontributestotheactivationofFLT3-ITD-dependentsignalingpathways.Mechanistically,circMYBL2enhancedthetranslationalefficiencyofFLT3kinasebyincreasingthebindingofPTBP1toFLT3mRNA.Moreover,circMYBL2knockdownimpairedthecytoactivityofinhibitor-resista...
