The ALDH2/PolG2 axis enhances mitochondrial biogenesis via transcriptional regulation of Nrf2 and promotes chemotherapy resistance in acute myeloid leukaemia

作者：X. Hu, Tianxing Hu, Shuyun Cao, Li Jiang, Yan Zhou, Qin Fang, J Wang · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07927-z · 被引用次数：5 · 研究领域：Acute Myeloid Leukemia Research、Histone Deacetylase Inhibitors Research、Epigenetics and DNA Methylation

Although patients with acute myeloid leukaemia (AML) initially respond to conventional treatments, many patients die from AML progression and relapsed/refractory (RR) disease. Eradicating AML thus remains therapeutically challenging. In this study, we found a strong expression of aldehyde dehydrogenase 2 (ALDH2) and increased mitochondrial biosynthesis in samples from patients with drug-resistant AML, and these changes were strongly associated with poor prognosis and recurrence of AML. We examined the clonogenic capacity, growth and apoptosis of AML cells, as well as mitochondrial DNA expression and reactive oxygen species production. Our results revealed that chemotherapeutic agents triggered the activation of NF-E2-related factor 2 (Nrf2) and promoted high expression of ALDH2, mediating the compensatory activation of mitochondrial respiration and resistance to chemotherapeutic agents in RR AML cells. Nrf2 promoted mitochondrial respiration by activating ALDH2 expression and stabilising the expression of DNA polymerase-gamma2 (PolG2) in mitochondria. Inhibition of the Nrf2-ALDH2/PolG2 pathway reduced AML metabolic fitness and oxidative phosphorylation levels, highlighting the key role of this pathway in promoting cell survival. Nrf2 inhibition reduced the translation of ALDH2, induced a unique mitochondrial stress response and inhibited mitochondrial biosynthesis in AML cells. Importantly, tumours in an in vivo xenograft model were sensitive to combined Nrf2 and ALDH2 inhibi...