Myosin‐IIA regulates leukemia engraftment and brain infiltration in a mouse model of acute lymphoblastic leukemia

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

关键词: cytoskeleton;    migration;    extravasation;    dissemination;    Bcr‐;    Abl;   

DOI  :  10.1189/jlb.1A0815-342R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Leukemiadissemination(thespreadofleukemiacellsfromthebonemarrow)andrelapseareassociatedwithpoorprognosis.Often,relapseoccursinperipheralorgans,suchastheCNS,whichactsasasanctuarysiteforleukemiacellstoescapeanti‐cancertreatments.Similartonormalleukocytemigration,leukemiadisseminationentailsmigrationofcellsfromthebloodcirculationintotissuesbyextravasation.Toextravasate,leukemiacellscrossthroughvascularendothelialwallsviaaprocesscalledtransendothelialmigration,whichrequirescytoskeletalremodeling.However,thespecificmolecularplayersinleukemiaextravasationarenotfullyknown.Weexaminedtheroleofmyosin‐IIAacytoskeletalclassIImyosinmotorprotein,inleukemiaprogressionanddisseminationintotheCNSbyuseofamousemodelofBcr‐Abl‐drivenBcellacutelymphoblasticleukemia.SmallhairpinRNA‐mediateddepletionofmyosin‐IIAdidnotaffectapoptosisorthegrowthrateofBcellacutelymphoblasticleukemiacells.However,inaninvivoleukemiatransfermodel,myosin‐IIAdepletionslowedleukemiaprogressionandprolongedsurvival,inpart,byreducingtheabilityofBcellacutelymphoblasticleukemiacellstoengraftefficiently.Finally,myosin‐IIAinhibition,eitherbysmallhairpinRNAdepletionorchemicalinhibitionbyblebbistatin,drasticallyreducedCNSinfiltrationofleukemiacells.Theeffectsonleukemiacellentryintotissuesweremostlyaresultoftherequirementformyosin‐IIAtoenableleukemiacellstocompletethetransendothelialmigrationprocessduringextravasation.Overall,ourdataimplicatemyosin‐IIAasakeymediatorofleukemiacellmigration,makingitapromisingtargettoinhibitleukemiadisseminationinvivoandpotentiallyreduceleukemiarelapses...

【 授权许可】

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