Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes

Abstract

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

Keywords: FLT3; IDH1; NPM1; acute myeloid leukemia; preclinical mouse model.