Targeting nucleotide metabolism and epigenetic regulation to overcome the differentiation blockade in AML.

Differentiation blockade is a central pathogenic hallmark of acute myeloid leukemia (AML). While all-trans retinoic acid (ATRA) achieves curative differentiation in acute promyelocytic leukemia (APL), this success has not extended to other AML subtypes. Recently, inhibitors targeting nucleotide metabolism-such as cytarabine, dihydroorotate dehydrogenase (DHODH) inhibitors, and DNA hypomethylating agents-have emerged as promising candidates to overcome this therapeutic barrier. These compounds promote myeloid maturation through mechanisms involving cell-cycle arrest, epigenetic reprogramming, and replication stress-activated signaling. Preclinical and early clinical evidence suggests that targeting nucleotide metabolism may induce partial differentiation of leukemic blasts, providing a metabolic and epigenetic avenue for therapy beyond APL. This mini-review summarizes current understanding of how metabolic inhibition restores differentiation in AML, focusing on representative agents and their mechanistic and translational implications. Targeting de novo nucleotide biosynthesis may offer a metabolic and epigenetic route to expand differentiation-based strategies beyond APL.