Biochemical, Epigenetic, and Metabolic Approaches to Target IDH Mutations in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a lethal hematologic malignancy associated with poor clinical outcomes. In recent years, mutations in the IDH1 and IDH2 genes have been discovered across a range of malignancies, including AML, raising hope for effective targeted therapies. An intriguing aspect of IDH1/2-mutant malignancies is the aberrant production of the oncometabolite 2-hydroxyglutarate (2-HG), which likely play a pivotal oncogenic role. We recently reported that 2-HG is dramatically elevated in the sera, marrow and urine of IDH1/2-mutant AML patients, and that levels of this oncometabolite directly correlate with disease burden and therapeutic response. The discovery of IDH1/2 mutations and their impact on important proteomic and metabolic pathways has triggered intensive efforts to develop novel and targeted therapies. IDH1/2 inhibitors are currently under early phase clinical investigation, with promising suggestion of efficacy. Other therapeutic approaches under preclinical and clinical investigation in this population include DNA methyltransferase inhibitors and agents that target glutamine metabolism through inhibition of glutaminase or depletion of serum glutamine by asparaginase products.