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

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

  • Cell Death Dis. 2025 Aug 13;16(1):616. doi: 10.1038/s41419-025-07927-z.
Xiuying Hu 1 2 3 4,  Tianzhen Hu 1 3 4,  Shuyun Cao 1 3 4,  Li Jiang 5,  Yan Zhou 6,  Qin Fang 7,  Jishi Wang 8 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China.
  • 2 School of Basic Medical Sciences, Guizhou Medical University, Guizhou, China.
  • 3 Hematological Institute of Guizhou Province, Guizhou, China.
  • 4 Guizhou Province Hematopoietic Stem Cell Transplantation Centre and Key Laboratory of Hematological Disease Diagnostic and Treatment Centre, Guizhou, China.
  • 5 Department of Pharmacy, Daqin Cancer Hospital of Guizhou Province, Guizhou, China.
  • 6 Department of Pediatric Nephrology and Rheumatology, Affiliated Hospital of Guizhou Medical University, Guizhou, China.
  • 7 Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guizhou, China. fangqin@gmc.edu.cn.
  • 8 Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China. wangjishi9646@163.com.
  • 9 School of Basic Medical Sciences, Guizhou Medical University, Guizhou, China. wangjishi9646@163.com.
  • 10 Hematological Institute of Guizhou Province, Guizhou, China. wangjishi9646@163.com.
  • 11 Guizhou Province Hematopoietic Stem Cell Transplantation Centre and Key Laboratory of Hematological Disease Diagnostic and Treatment Centre, Guizhou, China. wangjishi9646@163.com.
  • 12 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China. wangjishi9646@163.com.
PMID: 40796730 DOI: 10.1038/s41419-025-07927-z
Abstract

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 inhibition. Given the role of the Nrf2-ALDH2/PolG2 pathway in the progression of AML, inhibition of this pathway may prevent disease relapse/resistance and promote sensitisation to chemotherapy.

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