Mutant <i>IDH1</i> cooperates with <i>NPM1c</i> or <i>FLT3</i>^ITD to drive distinct myeloid diseases and molecular outcomes.

Abstract

In human acute myeloid leukemia (AML), mutations of isocitrate dehydrogenase-1 (<i>IDH1</i>) often co-occur with <i>NPM1</i> mutations, and less frequently with <i>FLT3</i> mutations. To investigate whether the effects of <i>IDH1</i> mutation differ according to the specific co-occurring mutation, we generated two strains of double knock-in mutant mice. <i>Idh1</i>^R132H combined with <i>Npm1c</i> induced overt AML, whereas <i>Idh1</i>^R132H plus <i>Flt3</i>^ITD resulted in <i>Flt3</i>^ITD-driven myelo- or lymphoproliferation that was minimally affected by <i>Idh1</i>^R132H and rarely generated AML. Gene expression profiling revealed differences between <i>Idh1</i>^R132H;<i>Npm1c</i> cells and <i>Idh1</i>^R132H;<i>Flt3</i>^ITD cells and suggested altered heme metabolism and immune responses in the former. The profile of <i>Idh1</i>^R132H;<i>Npm1c</i> cells corresponded to that of human <i>IDH</i>-mutated AML cells, particularly those resistant to inhibitors of mutant IDH. Compared to treatment with a menin inhibitor, IDH1-targeted therapy of <i>Idh1</i>^R132H;<i>Npm1c</i> AML-bearing mice was less efficacious in improving cell differentiation and extending survival. The differential cooperation of <i>Idh1</i>^R132H with <i>Npm1c</i> vs. <i>Flt3</i>^ITD may have implications for the devising of subtype-specific treatments for human AML.