biostudies-literatureBourgeois WNHLBI NIH HHSEuropean Hematology AssociationNCI NIH HHS1513-1527https://www.ebi.ac.uk/biostudies/studies/S-EPMC11033588biostudies-literatureUnknown143(15)<h4>Abstract</h4>Small molecules that target the menin-KMT2A protein-protein interaction (menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A or MLL1)-rearranged (KMT2A-r) and nucleophosmin-mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with menin inhibitors. Recently, the novel IKAROS degrader mezigdomide was developed with greatly enhanced IKAROS protein degradation. In this study, we show thatBloodMezigdomide is effective alone and in combination with menin inhibition in preclinical models of KMT2A-r and NPM1c AML.PMC11033588K99 CA279888P50 CA206963P01 CA066996R01 CA259273R01 CA176745R01 CA204639T32 HL007574F32 CA250240TRTH228K08 CA252174Wen YOlsen SNHatton CCrompton BDKirmani NEbert BLBourgeois WBoileau MArmstrong SAHenrich JAMcGeehan GMPerner FFischer ESPerry JASperling ASAubrey BJMartucci CApazidis AAPikman YCutler JANowak RPKlega KDonovan KAPollard JAWenge DVfalseMezigdomide is effective alone and in combination with menin inhibition in preclinical models of KMT2A-r and NPM1c AML.<h4>Abstract</h4>Small molecules that target the menin-KMT2A protein-protein interaction (menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A or MLL1)-rearranged (KMT2A-r) and nucleophosmin-mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with menin inhibitors. Recently, the novel IKAROS degrader mezigdomide was developed with greatly enhanced IKAROS protein degradation. In this study, we show that2024-01-01T00:00:00Z2024 Apr2026-06-02T07:57:28.215Z2026-04-16T03:11:26.073ZS-EPMC110335883809637110.1182/blood.2023021105