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

[摘要] InfiltrationofthecentralnervoussystemisaseveretraitofTcellacutelymphoblasticleukemia.InhibitionofCXCchemokinereceptor4significantlyamelioratesTcellacutelymphoblasticleukemiainmurinemodelsofthedisease;however,signalingbyCXCchemokinereceptor4isimportantinlimitingthedivagationofperipheralbloodmononuclearcellsoutoftheperivascularspaceintothecentralnervoussystemparenchyma.Therefore,InhibitionofCXCchemokinereceptor4potentiallymayuntangleTcellacutelymphoblasticleukemiacellsfromretentionoutsidethebrain.Here,weshowthatleukemiclymphoblastsmassivelyinfiltratecranialbonemarrow,withdiffusiontothemeningeswithoutinvasionofthebrainparenchyma,inmicethatunderwentxenotransplantationwithhumanTcellacutelymphoblasticleukemiacellsorthatdevelopedleukemiafromtransformedhematopoieticprogenitors.WetestedthehypothesisthatTcellacutelymphoblasticleukemianeuropathologyresultsfrommeningealinfiltrationthroughCXCchemokinereceptor4–mediatedbonemarrowcolonization.InhibitionofleukemiaengraftmentinthebonemarrowbypharmacologicCXCchemokinereceptor4antagonismsignificantlyamelioratedneuropathologicaspectsofthedisease.GeneticdeletionofCXCR4inmurinehematopoieticprogenitorsabrogatedleukemogenesisinducedbyconstitutivelyactiveNotch1,whereaslackofCCR6andCCR7,whichhavebeenshowntobeinvolvedinTcellandleukemiaextravasationintothecentralnervoussystem,respectively,didnotinfluenceTcellacutelymphoblasticleukemiadevelopment.WehypothesizethatlymphoblasticmeningealinfiltrationasaresultofbonemarrowcolonizationisresponsibleforthedegenerativealterationsoftheneuroparenchymaaswellasthealterationofcerebrospinalfluiddrainageinTcellacutelymphoblasticleukemiaxenografts.Therefore,CXCchemokinereceptor4mayconstituteapharmacologictargetforTcellacutelymphoblasticleukemianeuropathology...

[学科分类] 生理学

[关键词] meninges;neuropathology;blood‐brain barrier;CCR6;CCR7