Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society | |
Role of CXCR4‐mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia | |
关键词: meninges; neuropathology; blood‐; brain barrier; CCR6; CCR7; | |
DOI : 10.1189/jlb.5MA0915-394R | |
学科分类:生理学 | |
来源: Federation of American Societies for Experimental Biology | |
【 摘 要 】
InfiltrationofthecentralnervoussystemisaseveretraitofTcellacutelymphoblasticleukemia.InhibitionofCXCchemokinereceptor4significantlyamelioratesTcellacutelymphoblasticleukemiainmurinemodelsofthedisease;however,signalingbyCXCchemokinereceptor4isimportantinlimitingthedivagationofperipheralbloodmononuclearcellsoutoftheperivascularspaceintothecentralnervoussystemparenchyma.Therefore,InhibitionofCXCchemokinereceptor4potentiallymayuntangleTcellacutelymphoblasticleukemiacellsfromretentionoutsidethebrain.Here,weshowthatleukemiclymphoblastsmassivelyinfiltratecranialbonemarrow,withdiffusiontothemeningeswithoutinvasionofthebrainparenchyma,inmicethatunderwentxenotransplantationwithhumanTcellacutelymphoblasticleukemiacellsorthatdevelopedleukemiafromtransformedhematopoieticprogenitors.WetestedthehypothesisthatTcellacutelymphoblasticleukemianeuropathologyresultsfrommeningealinfiltrationthroughCXCchemokinereceptor4–mediatedbonemarrowcolonization.InhibitionofleukemiaengraftmentinthebonemarrowbypharmacologicCXCchemokinereceptor4antagonismsignificantlyamelioratedneuropathologicaspectsofthedisease.GeneticdeletionofCXCR4inmurinehematopoieticprogenitorsabrogatedleukemogenesisinducedbyconstitutivelyactiveNotch1,whereaslackofCCR6andCCR7,whichhavebeenshowntobeinvolvedinTcellandleukemiaextravasationintothecentralnervoussystem,respectively,didnotinfluenceTcellacutelymphoblasticleukemiadevelopment.WehypothesizethatlymphoblasticmeningealinfiltrationasaresultofbonemarrowcolonizationisresponsibleforthedegenerativealterationsoftheneuroparenchymaaswellasthealterationofcerebrospinalfluiddrainageinTcellacutelymphoblasticleukemiaxenografts.Therefore,CXCchemokinereceptor4mayconstituteapharmacologictargetforTcellacutelymphoblasticleukemianeuropathology...
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