Mutant cooperates with or to drive distinct myeloid diseases and molecular outcomes.

In human acute myeloid leukemia (AML), mutations of isocitrate dehydrogenase-1 () often co-occur with mutations, and less frequently with mutations. To investigate whether the effects of mutation differ according to the specific co-occurring mutation, we generated two strains of double knock-in mutant mice. combined with induced overt AML, whereas plus resulted in -driven myelo- or lymphoproliferation that was minimally affected by and rarely generated AML. Gene expression profiling revealed differences between ; cells and ; cells and suggested altered heme metabolism and immune responses in the former. The profile of ; cells corresponded to that of human -mutated AML cells, particularly those resistant to inhibitors of mutant IDH. Compared to treatment with a menin inhibitor, IDH1-targeted therapy of ; AML-bearing mice was less efficacious in improving cell differentiation and extending survival. The differential cooperation of with vs. may have implications for the devising of subtype-specific treatments for human AML.