Figure 1.

This figure demonstrates the effects of key mutations and the effect on cellular function. In the cytoplasm, isocitrate is converted to alpha-ketoglutarate (A-KG), but IDH1 mutations lead to the reduction of A-KG to D-2-hydroxyglutarate (D-2-HG) which is an oncometabolite that travels to the nucleus and inhibits TET2, which blocks DNA demethylation; additionally, D-2-HG is created via reduction in the mitochondria by IDH2 mutant enzymes from Krebs cycle-generated A-KG [77,78,79,80,81]. IDH1 inhibitors target the cytoplasmic reduction of A-KG to D-2-HG, while IDH2 inhibitors target the same but in the mitochondria [79,80,81]. NPM1, which normally resides in the nucleolus and minimally binds XPO1, can travel to the nucleoplasm in conditions of stress, where it inhibits HDM2; the inhibition of HDM2 is significant because the normal function of HDM2 is to inhibit TP53 [48,74]. Thus, by inhibiting HDM2, NPM1 can increase TP53 which has important implications for cell regulation in stressful conditions [48,74]. Mutant NPM1 (NPM1c) has a higher affinity to XPO1 and thus is prone to nuclear export, which leads to the export of important nuclear proteins [48,74]. Additionally, the consequent result of mutant NPM1, and XPO1-NPM1c, can lead to increased HOX expression [48,74]. Additionally, NPM1c and KMT2Ar interact with menin, which facilitates leukemogenic cellular changes; this can be targeted via menin inhibition [75]. This figure was adapted from the figures and text in the sources that are cited in this section.