The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells

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1、CancerCellArticleTheHistoneDemethylaseKDM1ASustainstheOncogenicPotentialofMLL-AF9LeukemiaStemCellsWilliamJ.Harris,1XuHuang,1JamesT.Lynch,1GaryJ.Spencer,1JamesR.Hitchin,2YaoyongLi,3FilippoCiceri,1JulianG.Blaser,1BrigitF.Greystoke,1AllanM.Jordan,2Crispin

2、J.Miller,3DonaldJ.Ogilvie,2andTimC.P.Somervaille1,*1CancerResearchUKLeukaemiaBiologyLaboratory2CancerResearchUKDrugDiscoveryUnit3CancerResearchUKAppliedComputationalBiologyandBioinformaticsGroupPatersonInstituteforCancerResearch,UniversityofManchester,

3、Manchester,M204BX,UnitedKingdom*Correspondence:tsomervaille@picr.man.ac.ukDOI10.1016/j.ccr.2012.03.014SUMMARYUsingamousemodelofhumanMLL-AF9leukemia,weidentifiedthelysine-specificdemethylaseKDM1A(LSD1orAOF2)asanessentialregulatorofleukemiastemcell(LSC)pot

4、ential.KDM1AactsatgenomiclociboundbyMLL-AF9tosustainexpressionoftheassociatedoncogenicprogram,thuspreventingdiffer-entiationandapoptosis.InvitroandinvivopharmacologictargetingofKDM1AusingtranylcypromineanalogsactiveinthenanomolarrangephenocopiedKdm1akn

5、ockdowninbothmurineandprimaryhumanAMLcellsexhibitingMLLtranslocations.Bycontrast,theclonogenicandrepopulatingpotentialofnormalhematopoieticstemandprogenitorcellswasspared.OurdataestablishKDM1AasakeyeffectorofthedifferentiationblockinMLLleukemia,whichma

6、ybeselectivelytargetedtotherapeuticeffect.INTRODUCTIONH3K4methyltransferaseMLL,itselfakeyepigeneticregulator,ismutatedbytranslocationinabout4%ofhumanAML.ThisEpigeneticdysfunctionhasacentralroleinthepathologyofresultsinconstitutivetranscriptionatMLLtarg

7、etgenesthroughmyeloidmalignancy.Thisisillustratedbythediscoveryofrecur-aberrantrecruitmentbyMLLfusionpartnersofproteinsandrentlyoccurringmutationstargetinggenesthatcodeforepige-complexesassociatedwithtranscriptionelongation,includingneticregulators,suc

8、hasthemethylcytosinehydroxylaseTET2,pTEFb,PAFc,andDOT1L,anH3K79methyltransferase(Yo-DNAmethyltransferaseDNMT3A,histoneH3K27methyltrans-koyamaetal.,2010;Linetal.,2010;Munteanetal.,2010).feraseEZH2,andPolycomb-relatedproteinASXL1.Mutation