Authors
Siyao Guo, Yutong Zou, Canfeng Zhang, Hui Han, Yishan Li, Yucong Sun, Zhaoyu Wang, Wanrui Zhang, Jiang Zhang, Yuli Gan, Qiang Zhang, Jieyi Ma, Siyi Zheng, Hongshen Qiu, Yan Zhu, Wange Lu, Yong Bao, Meng Zhao, Shuibin Lin
Published in
Nature cancer. Jul 15, 2026. Epub Jul 15, 2026.
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.
PMID:
42457944
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.
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