Role of CXCR4‐mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia

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

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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