Mutant IDH2 enzymes acquire a neomorphic enzymatic activity with the ability to produce 2-hydroxyglutarate from α-ketoglutarate, inhibiting multiple α-ketoglutarate-dependent dioxygenase reactions; leading to aberrant DNA hypermethylation and differentiation block in myeloid precursors and ultimately promoting leukemogenesis.
D2HG has been shown to promote leukemogenesis even in the absence of mutated IDH, but the prognostic significance of pretreatment serum D2HG levels in patients with IDH-mutated AML is unclear.
Our results establish a critical role for mutant IDH2 in leukemogenesis and tumor maintenance and identify an IDH-independent strategy to target these cancers therapeutically.