Lettershttps://doi.org/10.1038/s41591-018-0082-y1Tri-institutionalPhDPrograminChemicalBiology,MemorialSloanKetteringCancerCenter,NewYork,NY,USA.2ChemicalBiologyProgram,MemorialSloanKetteringCancerCenter,NewYork,NY,USA.3MolecularPharmacologyProgram,MemorialSloanKetteringCancerCenter,NewYork,NY,USA.4AntitumorAssessmentFacility,MemorialSloanKetteringCancerCenter,NewYork,NY,USA.5DepartmentofPediatrics,MemorialSloanKetteringCancerCenter,NewYork,NY,USA.6PharmacologyProgramoftheWeillCornellGraduateSchoolofMedicalSciences,MemorialSloanKetteringCancerCenter,NewYork,NY,USA.7Theseauthorscontributedequally:DarrenC.Johnson,CorneliusY.Taabazuing.*e-mail:bachovcd@mskcc.orgSmall-moleculeinhibitorsoftheserinedipeptidasesDPP8andDPP9(DPP8/9)inducealyticformofcelldeathcalledpyroptosisinmouseandhumanmonocytesandmacro-phages1,2.Inmousemyeloidcells,Dpp8/9inhibitionactivatestheinflammasomesensorNlrp1b,whichinturnactivatespro-caspase-1tomediatecelldeath3,butthemechanismofDPP8/9inhibitor-inducedpyroptosisinhumanmyeloidcellsisnotyetknown.HereweshowthattheCARD-containingproteinCARD8mediatesDPP8/9inhibitor-inducedpro-caspase-1-dependentpyroptosisinhumanmyeloidcells.WefurthershowthatDPP8/9inhibitorsinducepyroptosisinthemajorityofhumanacutemyeloidleukemia(AML)celllinesandprimaryAMLsamples,butnotincellsfrommanyotherlineages,andthattheseinhibitorsinhibithumanAMLprogressioninmousemodels.Overall,thisworkidentifiesanactivatorofCARD8inhumancellsandindicatesthatitsacti-vationbysmall-moleculeDPP8/9inhibitorsrepresentsanewpotentialtherapeuticstrategyforAML.Val-boroPro(Fig.1a,alsocalledPT-100andtalabostat)isanon-selectiveinhibitorofthepost-prolinecleavingserinepro-teases4–6thatinducesanticancerimmuneresponsesinsyngeneicmousetumormodels7,8.Inmice,Val-boroProincreasestheserumproteinlevelsofseveralcytokines,includingG-CSFandCxcl1,andthesecytokinesarethoughttodrivetumor-specificimmu-nity7.WerecentlydiscoveredthatinhibitionoftwointracellularserinedipeptidasesDpp8andDpp9(Dpp8/9)byVal-boroProactivatestheinfla...
