PAPOLA-mediated hyperactive polyadenylation promotes leukemogenesis and leukemia stem cell self-renewal through metabolic reprogramming

Abstract

Polyadenylation is essential for mRNA stability and translational efficiency. Although poly(A) tail length is dynamically regulated under physiological conditions, its dysregulation and functional importance in cancer remain poorly understood. Here, we identify widespread poly(A) tail elongation and aberrant upregulation of poly(A) polymerase alpha (PAPOLA) in acute myeloid leukemia (AML), with high PAPOLA expression associated with poor clinical outcomes. Using primary AML samples, leukemia cell lines and multiple mouse models, we demonstrate that PAPOLA-driven hyperactive polyadenylation promotes leukemogenesis and sustains leukemia stem cell maintenance. Mechanistically, PAPOLA enhances metabolic reprogramming by upregulating glutathione S-transferase mu 2 (GSTM2), which activates the 4-hydroxynonenal (HNE)–dihydrolipoamide dehydrogenase (DLD) axis to drive AML progression. Notably, pharmacological inhibition of PAPOLA with cordycepin suppresses metabolic reprogramming and impairs leukemogenesis. Overall, our findings establish hyperactive polyadenylation as a core oncogenic mechanism linking RNA processing to cancer metabolism in AML, highlighting the PAPOLA–GSTM2–HNE–DLD axis as a promising therapeutic target. Using in vivo acute myeloid leukemia models, Guo et al show that the targetable poly(A) polymerase alpha mediates hyperadenylation of the mRNA for the antioxidant protein glutathione S-transferase mu 2, thereby supporting leukemia stem cell maintenance through activation of the tricarboxylic acid cycle.