Transcriptomics and Metabolomics Analysis to Explore the Ferroptosis Susceptibility of Venetoclax-Resistant AML Cells.
10.19746/j.cnki.issn.1009-2137.2025.03.001
- Author:
Yue LI
1
;
Jia-Qi WAN
1
;
Xin-Tong YANG
1
;
Bao-Quan SONG
2
;
Fei LI
2
;
Hong-Wei PENG
1
Author Information
1. Department of Pharmacy, The First Affiliated Hospital of Jiangxi Medical College, Nanchang University,Nanchang 330000, Jiangxi Province, China.
2. Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital of Jiangxi Medical College, Nanchang University, Nanchang 330000, Jiangxi Province, China.
- Publication Type:Journal Article
- Keywords:
acute myeloid leukemia;
venetoclax resistance;
ferroptosis;
transcriptomics;
metabolomics
- MeSH:
Humans;
Ferroptosis;
Leukemia, Myeloid, Acute/metabolism*;
Sulfonamides/pharmacology*;
Bridged Bicyclo Compounds, Heterocyclic/pharmacology*;
Drug Resistance, Neoplasm;
Metabolomics;
Cell Line, Tumor;
Phospholipid Hydroperoxide Glutathione Peroxidase;
Amino Acid Transport System y+/metabolism*;
Transcriptome
- From:
Journal of Experimental Hematology
2025;33(3):621-632
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To investigate the susceptibility of venetoclax-resistant acute myeloid leukemia (AML) cell lines to ferroptosis and to uncover the underlying molecular mechanisms using transcriptomic and metabolomic analysis methods.
METHODS:Venetoclax-resistant AML cell lines were constructed using a low-dose concentration escalation method. The sensitivity of cells to chemotherapeutic drugs was detected by CCK-8 assay. The susceptibility of drug-resistant cell lines to ferroptosis was assessed using transcriptomic and metabolomic analysis methods. The expression of cellular GPX4 and SLC7A11 protein was detected by Western blot, and cell death and lipid peroxidation levels were measured by flow cytometry. Depmap database and TCGA cohort were applied to explore the effect of ferroptosis-related genes expression on prognosis.
RESULTS:Venetoclax-resistant cell lines exhibited sensitivity to ferroptosis inducers RSL3, APR246, and sorafenib. The ferroptosis inhibitor Fer-1 partially inhibited cell death induced by these inducers. Compared with the parental cells, significant changes in metabolites and gene expression levels related to ferroptosis were observed in the resistant cell lines. In particular, deregulated expression of SLC7A11 and GPX4 may play critical role in ferroptosis susceptibility. Besides, GPX4 was identified as more important for AML cell survival and higher GPX4 expression may predict shortened overall survival, NPM1 mutant and IDH1 R132 mutation positive patients may prone to possess higher GPX4 expression.
CONCLUSION:Venetoclax-resistant AML cell lines remain susceptible to ferroptosis, higher GPX4 expression maybe a critical marker for poor prognosis. Regulating the expression of ferroptosis-related genes and metabolites may enhance the efficacy of venetoclax and provide new treatment options for AML patients.
