The double bromodomain protein Brd2 promotes B cell expansion and mitogenesis

[摘要] Bromodomain‐containingtranscriptionalregulatorsrepresentnewepigenetictargetsindifferenthematologicmalignancies.However,bromodomain‐mediatedmechanismsthatcouplehistoneacetylationtotranscriptioninlymphopoiesisandgovernmaturelymphocytemitogenesisarepoorlyunderstood.Brd2,atranscriptionalcoregulatorthatcontainsdualbromodomainsandanextraterminaldomain(theBETfamily),coupleschromatintocell‐cycleprogression.WereportedpreviouslythefirstfunctionalcharacterizationofaBETproteinasaneffectorofmammalianmitogenicsignaltransduction:Eμ‐Brd2Tgmicedevelop“activatedBcell”diffuselargeBcelllymphoma.NootheranimalmodelsexistforgeneticorlentiviralexpressionofBETproteins,hamperingtestingofnovelanti‐BETanticancerdrugs,suchasJQ1.WetransducedHSCswithBrd2lentivirusandreconstitutedrecipientmicetotestthehypothesisthatBrd2regulateshematopoiesisinBMandmitogenesisintheperiphery.ForcedexpressionofBrd2providesanexpansionadvantagetothedonor‐derivedBcellcompartmentinBMandincreasesmatureBcellmitogenicresponsivenessinvitro.Brd2bindsthecyclinApromoterinBcells,shownbyChIP,andincreasescyclinAmRNAandproteinlevels,andS‐phaseprogressioninvitroinmitogen‐stimulatedprimaryBcells,butnotTcells,reinforcingresultsfromEμ‐Brd2mice.ThesmallmoleculeBETinhibitorJQ1reducesBcellmitogenesis,consistentwiththeinterpretationthatBETinhibitorsareantiproliferative.Brd2‐specificknockdownexperimentsshowthatBrd2isalsorequiredforhematopoiesis.WeconcludethatBrd2playsacritical,independentroleinregulationofmitogenicresponsegenes,particularlycyclinA,inBcells...

[学科分类] 生理学

[关键词] B‐lymphopoiesis;immune reconstitution;BET proteins;chromatin;hematopoietic stem cells;side population