Therapeutic efficacy of FTY720 in a rat model of n

doi:10.1182/blood-2011-01-331447PrepublishedonlineJuly18,2011;    MarkKester,DhimantDesai,ShantuAmin,ThomasP.Loughran,Jr.andXinLiuLoughran,LeahHirsch,NancyRuthJarbadan,KendallThomasBaab,JasonLiao,Hong-GangWang,Zhang,YongpingLi,LindsayRyland,JunYang,CesarAliaga,AldenDewey,AndrewRogers,KellyAijunLiao,KathleenBroeg,ToddFox,Su-FernTan,RebeccaWatters,MithunVinodShah,LucyQ. TherapeuticefficacyofFTY720inaratmodelofnaturalkillercellleukemia:::digitalobjectidentifier(DOIs)anddateofinitialpublication.theindexedbyPubMedfrominitialpublication.CitationstoAdvanceonlinearticlesmustincludefinalpublication).Advanceonlinearticlesarecitableandestablishpublicationpriority;theyareappearedinthepaperjournal(edited,typesetversionsmaybepostedwhenavailablepriortoAdvanceonlinearticleshavebeenpeerreviewedandacceptedforpublicationbuthavenotyetCopyright2011byTheAmericanSocietyofHematology;allrightsreserved.20036.theAmericanSocietyofHematology,2021LSt,NW,Suite900,WashingtonDCBlood(printISSN0006-4971,onlineISSN1528-0020),ispublishedweeklyby    Forpersonaluseonly.atShanghaiInformationCenterforLifeSciences,CASonAugust14,2011.bloodjournal.hematologylibrary.orgFrom1TherapeuticefficacyofFTY720inaratmodelofnaturalkillercellleukemiaShorttitleTherapeuticEfficacyofFTY720inNKCellleukemiaAijunLiao1,2,KathleenBroeg1,ToddFox1,3,Su-FernTan1,RebeccaWatters1,MithunVinodShah1,LucyQ.Zhang1,YongpingLi1,LindsayRyland1,3,JunYang1,CesarAliaga1,AldenDewey1,AndrewRogers1,KellyLoughran1,LeahHirsch1,NancyRuthJarbadan1,KendallThomasBaab1,JasonLiao1,Hong-GangWang1,3,MarkKester1,3,DhimantDesai1,3,ShantuAmin1,3,ThomasP.Loughran,Jr1,XinLiu11.PennStateHersheyCancerInstitute,PennsylvaniaStateUniversityCollegeofMedicine,Hershey,PA17033;2.DepartmentofHematology,ShengjingHospitalofChinaMedicalUniversity,Shenyang,Liaoningprovince110004,P.R.China;3.DepartmentofPharmacology,PennsylvaniaStateUniversityCollegeofMedicine,Hershey,PA17033Correspondingauthor:XinLiuPennStateHersheyCancerInstituteExperimentalTherapeutics-CH74Room4401500UniversityDrivePOBox850Hershey,[e-mail]:717-531-3073Fax:[phone]BloodFirstEditionPaper,prepublishedonlineJuly18,2011;DOI10.1182/blood-2011-01-331447Copyright©2011AmericanSocietyofHematologyForpersonaluseonly.atShanghaiInformationCenterforLifeSciences,CASonAugust14,2011.bloodjournal.hematologylibrary.orgFrom2AbstractNaturalkiller(NK)cellleukemiaisaclonalexpansionofNKcells.Theillnesscanoccurinanaggressiveorchronicform.WestudiedcelllinesfromhumanandratNKcellleukemias(aggressiveNKcellleukemia)aswellassamplesfrompatientswithchronicNKcellleukemiatoinvestigatepathogenicmechanisms.HerewereportthatMcl-1wasoverexpressedinleukemicNKcellsandthatknockdownofMcl-1inducedapoptosisintheseleukemiccells.InvitrotreatmentofhumanandratNKleukemiacellswithFTY720ledtocaspase-dependentapoptosisanddecreasedMcl-1expression,inatime-and-dose-dependentmanner.Thesebiologiceffectscouldbeinhibitedbyblockadeofreactiveoxygenspeciesgenerationandthelysosomaldegradationpathway.LipidomicanalysesafterFTY720treatmentdemonstratedelevatedlevelsofsphingosine,whichmediatedapoptosisofleukemicNKcellsinvitro.Importantly,systemicadministrationofFTY720inducedcompleteremissioninthesyngeneicFischerratmodelofNK-cellleukemia.TherapeuticefficacywasassociatedwithdecreasedexpressionofMcl-1invivo.ThesedatademonstratethattherapeuticbenefitofFTY720mayresultfrombothalteredsphingolipidmetabolismaswellasenhanceddegradationofakeycomponentofsurvivalsignaling.IntroductionLargegranularlymphocyte(LGL)leukemiaisaclonaldiseaserepresentingaspectrumofbiologicallydistinctlymphoproliferativediseasesoriginatingeitherfrommatureTcellsCD3+ornaturalkiller(NK)cellsCD3−.BothCD3+andCD3-LGLfunctionascytotoxiclymphocytes.The2008WorldHealthClassificationofmatureT-andNK-cellneoplasmscontinuestodistinguishT-cellLGLleukemia(T-LGLleukemia)fromaggressiveNK-cellleukemiabasedontheiruniquemolecularandclinicalfeatures.Furthermore,anewprovisionalentityofchroniclymphoproliferativedisorderofNKcells(alsoknownaschronicNKcelllymphocytosisorchronicNK-LGLleukemia)wascreatedtodistinguishitfrommuchmoreForpersonaluseonly.atShanghaiInformationCenterforLifeSciences,CASonAugust14,2011.bloodjournal.hematologylibrary.orgFrom3aggressiveNK-cellleukemia.1BothaggressiveNK-cellleukemiaandchronicNK-cellleukemiadisplayCD3-CD56+immunophenotype.1AggressiveNK-cellleukemiaisafatalillnesswhichpursuesaverymalignantclinicalcoursecharacterizedbyrefractorinesstoconventionalchemotherapy,andashortmediansurvivaltimeof2months.2-4Therearenoeffectivetherapiesforthisdisorderandpathogeneticmechanismsremainundefined.FTY720hasrecentlyshownpre-clinicalac