Notch Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation 英文参考文献.docVIP

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Notch Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation 英文参考文献.doc

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Notch Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation 英文参考文献

NotchAnkyrinRepeatDomainVariationInfluences LeukemogenesisandMycTransactivation JonC.Aster1*,NickBodnar3,4,LanweiXu2,FredrickKarnell2,JohnM.Milholland2,IvanMaillard2 ,Gavin Histen1,YunsunNam4,StephenC.Blacklow1,3,4,WarrenS.Pear2* 1DepartmentofPathology,BrighamandWomen’sHospital,Boston,Massachusetts,UnitedStatesofAmerica,2DepartmentofPathologyandLabMedicine,Abramson FamilyCancer Research Institute,Institute for Medicine and Engineering, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United StatesofAmerica,3DepartmentofCancerBiology,DanaFarberCancerInstitute,Boston,Massachusetts,UnitedStatesofAmerica,4DepartmentofBiologicalChemistry andMolecularPharmacology,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica Abstract Background:ThefunctionalinterchangeabilityofmammalianNotchreceptors(Notch1-4)innormalandpathophysiologic contextssuchascancerisunsettled.Weusedcomplementary invivo,cell-based andstructuralanalysestocomparethe abilities of activated Notch1-4 tosupport T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T- ALL),andmaintainT-ALLcellgrowthandsurvival. PrincipalFindings:WefindthattheactivatedintracellulardomainsofNotch1-4(ICN1-4)allsupportTcelldevelopmentin miceandthymicorganculture.However,unlikeICN1-3,ICN4failstoinduceT-cellacutelymphoblasticleukemia/lymphoma (T-ALL)andisunabletorescuethegrowthofNotch1-dependentT-ALLcelllines.TheICN4phenotypeismimickedbyweak gain-of-functionformsofNotch1,suggestingthatitstemsfromafailuretotransactivateoneormorecriticaltargetgenes above a necessary threshold. Experiments with chimeric receptors demonstrate that the Notch ankyrin repeat domains differintheirleukemogenicpotential,andthatthisdifferencecorrelateswithactivationofMyc,adirectNotchtargetthat hasanimportantroleinNotch-associatedT-ALL. Conclusions/Significance:WeconcludethattheleukemogenicpotentialsofNotchreceptorsvary,andthatthisfunctional differencestemsinpartfromdivergenceamongthehighlycon