Mutant and wild-type isocitrate dehydrogenase 1 share enhancing mechanisms involving distinct tyrosine kinase cascades in cancer

Isocitrate dehydrogenase 1 (IDH1) is important for reductive carboxylation in cancer cells, and IDH1 R132H mutant plays a pathogenic role in cancers including acute myeloid leukemia (AML). However, the regulatory mechanisms modulating IDH1 mutant and/or wild-type (WT) function remain unknown. Here we show that two groups of tyrosine kinases (TKs) enhance the activation of IDH1 mutant and WT through preferential Y42 or Y391 phosphorylation. Mechanistically, Y42 phosphorylation occurs in IDH1 monomers, which promotes dimer formation with enhanced substrate (isocitrate or a-ketoglutarate) binding, while Y42-phosphorylated dimers show attenuated disruption to monomers. Y391 phosphorylation occurs in both monomeric and dimeric IDH1, which enhances cofactor (NADP+ or NADPH) binding. Diverse oncogenic TKs activate Src to achieve Y42 and Y391 phosphorylation of IDH1, respectively, which contributes to reductive carboxylation and tumor growth, while FLT3 or FLT3-ITD mutant activate JAK2 to enhance IDH1 mutant activity through phosphorylation of Y391 and Y42, respectively, in AML cells.