AML1ETO Oncoprotein Is Directed to AML1 Binding Regions and Co-Localizes with AML1 and HEB on Its Targets 英文参考文献.docVIP

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AML1ETO Oncoprotein Is Directed to AML1 Binding Regions and Co-Localizes with AML1 and HEB on Its Targets 英文参考文献.doc

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AML1ETO Oncoprotein Is Directed to AML1 Binding Regions and Co-Localizes with AML1 and HEB on Its Targets 英文参考文献

AML1/ETOOncoproteinIsDirectedtoAML1Binding RegionsandCo-LocalizeswithAML1andHEBonIts Targets AlessandroGardini1,MatteoCesaroni1,LucillaLuzi2,AkikoJ.Okumura3,JosephR.Biggs3,SimoneP. Minardi2,4,ElisaVenturini4,Dong-ErZhang3,PierGiuseppePelicci1,5,MyriamAlcalay1,4,5 * 1Department of Experimental Oncology, IEO–European Institute of Oncology, Milan, Italy, 2IFOM–FIRC Institute for Molecular Oncology Foundation, Milan, Italy, 3Moores UCSD Cancer Center, Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America,4Cogentech–ConsortiumforGenomicTechnologies,Milan,Italy,5DipartimentodiMedicina,ChirurgiaeOdontoiatria,Universita` degliStudidiMilano,Milan, Italy Abstract Areciprocaltranslocationinvolvingchromosomes8and21generatestheAML1/ETOoncogenictranscriptionfactorthat initiatesacutemyeloidleukemiabyrecruitingco-repressorcomplexestoDNA.AML1/ETOinterfereswiththefunctionofits wild-typecounterpart,AML1,bydirectlytargetingAML1bindingsites.However,transcriptionalregulationdeterminedby AML1/ETOprobablyreliesonamorecomplexnetwork,sincethefusionproteinhasbeenshowntointeractwithanumber ofothertranscriptionfactors,inparticularE-proteins,andmaythereforetargetothersitesonDNA.Genome-widechromatin immunoprecipitationandexpressionprofilingwereexploitedtoidentifyAML1/ETO-dependenttranscriptionalregulation. AML1/ETOwasfoundtoco-localizewithAML1,demonstratingthatthefusionproteinfollowsthebindingpatternofthe wild-typeproteinbutdoesnotfunctionprimarilybydisplacingit.TheDNAbindingprofileoftheE-proteinHEBwasgrossly rearrangeduponexpressionofAML1/ETO,andthefusionproteinwasfoundtoco-localizewithbothAML1andHEBon many of its regulated targets. Furthermore, the level of HEB protein was increased in both primary cells and cell lines expressingAML1/ETO.OurresultssuggestamajorroleforthefunctionalinteractionofAML1/ETOwithAML1andHEBin transcriptionalregulationdeterminedbythefusionprotein. Citation:GardiniA,Cesaroni