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Exploring Experimental Hematology: June 2021 (Volume 98)

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DNA methylation therapy joins forces in IDH2 -mutant AML Isocitrate dehydrogenases 1 and 2 ( IDH1 /2) are frequently mutated in Acute Myeloid Leukemia (AML), with nearly 20% of patients carrying gain-of-function point mutations in these genes (Ley et al., 2013) . IDH2 is a metabolic enzyme that catalyzes the conversion of isocitrate to 2-oxoglutarate during the Krebs cycle. Patients carrying IDH2 gain-of-function mutations produce instead high levels of the oncometabolite 2-hydroxyglutarate (2-HG), which inhibits oxoglutarate-dependent enzymes such as the TET family of methylcytosine dioxygenases, responsible for active DNA demethylation (Xu et al., 2011) . As a consequence, IDH2 mutations in AML patients induce DNA hypermethylation and inhibit hematopoietic differentiation (Figueroa et al., 2010) . Azacytidine (AZA) and enasidenib (ENA) are commonly used AML therapies which induce DNA hypomethylation, albeit through different mechanisms. AZA is a nucleoside analog that inhibits