Association of Reactive Oxygen Species-Mediated Signal Transduction with In Vitro Apoptosis Sensitivity in Chronic Lymphocytic Leukemia B Cells 英文参考文献.docVIP
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Association of Reactive Oxygen Species-Mediated Signal Transduction with In Vitro Apoptosis Sensitivity in Chronic Lymphocytic Leukemia B Cells 英文参考文献
AssociationofReactiveOxygenSpecies-MediatedSignal
TransductionwithInVitroApoptosisSensitivityin
ChronicLymphocyticLeukemiaBCells
AdamL.Palazzo1.,ErikEvensen1.,Ying-WenHuang1,AlessandraCesano1,GarryP.Nolan2,WendyJ.
Fantl1,2
*
1NodalityInc.,SouthSanFrancisco,California,UnitedStatesofAmerica,2BaxterLaboratoryforStemCellBiologyandDepartmentofMicrobiologyandImmunology,
StanfordUniversity,PaloAlto,California,UnitedStatesofAmerica
Abstract
Background:Chroniclymphocyticleukemia(CLL)isaBcellmalignancywithavariableclinicalcourseandunpredictable
response to therapeutic agents. Single cell network profiling (SCNP) utilizing flow cytometry measures alterations in
signalingbiologyinthecontextofmolecularchangesoccurringinmalignancies.InthisstudySCNPwasusedtoidentify
proteomicprofilesassociatedwithinvitroapoptoticresponsivenessofCLLBcellstofludarabine,asabasisforultimately
linkingthesewithclinicaloutcome.
Methodology/PrincipalFinding:SCNPwasusedtoquantifymodulated-signalingofBcellreceptor(BCR)networkproteins
andinvitroF-ara-Amediatedapoptosisin23CLLsamples.Ofthemodulatorsstudiedthereactiveoxygenspecies,hydrogen
peroxide (H2O2), a known intracellular second messenger and a general tyrosine phosphatase inhibitor stratified CLL
samplesintotwosub-groupsbasedonthepercentageofBcellsinaCLLsamplewithincreasedphosphorylationofBCR
networkproteins.Separately,inthesamepatientsamples,invitroexposuretoF-ara-Aalsoidentifiedtwosub-groupswithB
cellsshowingcompetenceorrefractorinesstoapoptoticinduction.StatisticalanalysisshowedthatinvitroF-ara-Aapoptotic
proficiencywashighlyassociatedwiththeproficiencyofCLLBcellstoundergoH2O2-augmentedsignaling.
Conclusions/Significance:ThislinkageinCLLBcellsamongthemechanismsgoverningchemotherapy-inducedapoptosis
increasedsignalingofBCRnetworkproteinsandalikelyroleofphosphataseactivitysuggestsameansofstratifyingpatients
fortheirresponsetoF-ara-Abasedregimens.Futurestudieswillexaminetheclinicalapplicabilityofthesefindingsandalso
theutilityofthisapproachinrelatingm
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