ASS1-derived argininosuccinate promotes purine nucleoside synthesis in B cell acute lymphoblastic leukaemia.

Metabolic remodelling underlies tumour progression. However, how metabolites act as signalling molecules to support cancer cell proliferation remains unclear. Here we show that argininosuccinate (ASA), a key intermediate of the urea cycle, promotes purine nucleoside biosynthesis in tyrosine kinase-driven haematological malignancies. Mechanistically, BCR-ABL phosphorylates argininosuccinate synthase 1 (ASS1), which increases ASA production from citrulline. ASA directly binds cytosolic 5'-nucleotidase II (NT5C2) and enhances its nucleosidase activity. The resulting purine nucleosides serve as a carbon source for glycolysis and the tricarboxylic acid cycle, which supports leukaemia cell proliferation under glucose-replete conditions. Loss of ASS1 or NT5C2 disrupts central carbon metabolism and inhibits leukaemia progression in vivo, which can be rescued with inosine or adenosine supplementation. Collectively, our findings uncover an ASA-NT5C2 signalling axis linking urea cycle dysregulation to purine metabolism, and identify purine nucleosides as a carbon source in tyrosine kinase-driven haematological malignancies.