Pronounced Hypoxia in Models of Murine and Human Leukemia High Efficacy of Hypoxia-Activated Prodrug PR-104 英文参考文献.docVIP

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Pronounced Hypoxia in Models of Murine and Human Leukemia High Efficacy of Hypoxia-Activated Prodrug PR-104 英文参考文献.doc

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Pronounced Hypoxia in Models of Murine and Human Leukemia High Efficacy of Hypoxia-Activated Prodrug PR-104 英文参考文献

PronouncedHypoxiainModelsofMurineandHuman Leukemia:HighEfficacyofHypoxia-ActivatedProdrug PR-104 JulianaBenito1,YuexiShi1,BarbaraSzymanska5,HernanCarol5,IngridBoehm5,HongboLu1 ,Sergej Konoplev3,WendyFang4,PatrickA.Zweidler-McKay4,DarioCampana6,GautamBorthakur1 ,Carlos Bueso-Ramos3,ElizabethShpall2,DeborahA.Thomas1,CraigT.Jordan7,HagopKantarjian1,WilliamR. Wilson8,RichardLock8,MichaelAndreeff1,2,MarinaKonopleva1,2 * 1SectionofMolecularHematologyandTherapy,DepartmentofLeukemia,TheUniversityofTexasMDAndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica, 2Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America, 3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America, 4Department of Pediatrics, The UniversityofTexasMDAndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica,5C25LowyCancerResearchCentre,Children’sCancerInstituteAustraliafor MedicalResearch,UniversityofNewSouthWales,Randwick,NewSouthWales,Australia,6St.JudeChildren’sResearchHospital,Memphis,Tennessee,UnitedStatesof America,7SchoolofMedicineandDentistry,UniversityofRochester,Rochester,NewYork,UnitedStatesofAmerica, 8AucklandCancerSocietyResearchCenter,The UniversityofAuckland,Auckland,NewZealand Abstract Recentstudiesindicatethatinteractionsbetweenleukemiacellsandthebonemarrow(BM)microenvironmentpromote leukemiacellsurvivalandconferresistancetoanti-leukemicdrugs.ThereisevidencethatBMmicroenvironmentcontains hypoxicareasthatconfersurvivaladvantagetohematopoieticcells.Inthepresentstudyweinvestigatedwhetherhypoxia in leukemic BM contributes to the protective role of the BM microenvironment. We observed a marked expansion of hypoxicBMareasinimmunodeficientmiceengraftedwithacutelymphoblasticleukemia(ALL)cells.Consistentwiththis finding, we found that hypoxia promotes chemoresistance in various ALL derived cell lines. These findings sugge