AG-221 as an effective and on-target therapy in IDH2 mutant AML. Mus musculus

Herein we developed a multigenic AML model with inducible expression of IDH2R140Q and constitutive expression of mutant DNMT3AR882H and NRASG12D. Using genetic de-induction and the first-in-class IDH2 inhibitor AG-221, we demonstrate that despite the presence of multiple oncogenic lesions, AML cells expressing mutant IDH2 depend on continued production of 2-HG to maintain their leukemic potential. Moreover, by comparing pharmacological inhibition and genetic depletion of IDH2R140Q we validate AG-221 as a highly on target inhibitor and identify key downstream pathways including GATA1 that are critical for disease maintenance. Overall design: RNA sequencing of mutant IDH2 AML cells treated with vehicle, doxycycline (genetic depletion of IDH2R140Q) or AG-221 (IDH2 inhibitor)