Abstract
Differentiation arrest represents a distinct hallmark of acute myeloid leukemia (AML). Identification of differentiation-induction agents that are effective across various subtypes remains an unmet challenge. GTP biosynthesis is elevated in several types of cancers, considered to support uncontrolled tumor growth. Here we report that GTP overload by supplementation of guanosine, the nucleoside precursor of GTP, poises AML cells for differentiation and growth inhibition. Transcriptome profiling of guanosine-treated AML cells reveals a myeloid differentiation pattern. Importantly, the treatment compromises leukemia progression in AML xenograft models. Mechanistically, GTP overproduction requires sequential metabolic conversions executed by the purine salvage biosynthesis pathway including the involvement of purine nucleoside phosphorylase (PNP) and hypoxanthine phosphoribosyltransferase 1 (HPRT1). Taken together, our study offers novel metabolic insights tethering GTP homeostasis to myeloid differentiation and provides an experimental basis for further clinical investigations of guanosine or guanine nucleotides in the treatment of AML patients.