The tumor suppressor gene DAPK2 is induced by the myeloid transcription factors PU.1 and C/EBPα during granulocytic differentiation but repressed by PML‐RARα in APL

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: APL;    neutrophil;    acute myeloid leukemia;    DRP‐;    1;   

DOI  :  10.1189/jlb.1112608

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

DAPK2isaproapoptoticproteinthatismostlyexpressedinthehematopoietictissue.AdetailedDAPK2expressionanalysisintwolargeAMLpatientcohortsrevealedparticularlylowDAPK2mRNAlevelsinAPL.DAPK2levelswererestoredinAPLpatientsundergoingATRAtherapy.PML‐RARAisthepredominantlesioninAPLcausingtranscriptionalrepressionofgenesimportantforneutrophildifferentiation.WefoundbindingofPML‐RARAandPU.1,amyeloidmasterregulator,toRARAandPU.1bindingsitesintheDAPK2promoter.EctopicexpressionofPML‐RARAinnon‐APL,aswellasknockingdownPU.1inAPLcells,resultedinasignificantreductionofDAPK2expression.RestoringDAPK2expressioninPU.1knockdownAPLcellspartiallyrescuedneutrophildifferentiation,therebyidentifyingDAPK2asarelevantPU.1downstreameffector.Moreover,lowDAPK2expressionisalsoassociatedwithC/EBPα‐mutatedAMLpatients,andwefoundC/EBPα‐dependentregulationofDAPK2duringAPLdifferentiation.Inconclusion,weidentifiedfirstinhibitorymechanismsresponsibleforthelowDAPK2expressioninparticularAMLsubtypes,andtheregulationofDAPK2bytwomyeloidtranscriptionfactorsunderlinesitsimportanceinneutrophildevelopment...

【 授权许可】

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