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

Abstract

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.