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[Transcriptomics and Metabolomics Analysis to Explore the Ferroptosis Susceptibility of Venetoclax-Resistant AML
Yue Li1,2, Jia-Qi Wan1,2, Xin-Tong Yang1,2
1Department of Pharmacy, The First Affiliated Hospital of Jiangxi Medical College, Nanchang University,Nanchang 330000, Jiangxi Province, China.
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.
Insights
Venetoclax-resistant acute myeloid leukemia (AML) cells remain susceptible to ferroptosis. Higher glutathione peroxidase 4 (GPX4) expression indicates a poor prognosis in AML patients, suggesting new therapeutic avenues.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Context:
- Venetoclax resistance is a significant challenge in treating acute myeloid leukemia (AML).
- Ferroptosis, a regulated form of cell death, presents a potential therapeutic target.
- Understanding the mechanisms of resistance and alternative cell death pathways is crucial for improving AML treatment outcomes.
Purpose:
- To investigate the susceptibility of venetoclax-resistant AML cell lines to ferroptosis.
- To elucidate the molecular mechanisms underlying this susceptibility using transcriptomic and metabolomic analyses.
- To explore the prognostic implications of ferroptosis-related gene expression in AML.
Summary:
- Venetoclax-resistant AML cell lines demonstrated sensitivity to ferroptosis inducers, with partial inhibition by Fer-1.
- Transcriptomic and metabolomic analyses revealed significant alterations in ferroptosis-related pathways, particularly involving SLC7A11 and GPX4.
- Elevated GPX4 expression was linked to reduced overall survival and associated with specific mutations (NPM1, IDH1 R132).
Impact:
- This study identifies ferroptosis as a viable therapeutic strategy for venetoclax-resistant AML.
- GPX4 emerges as a potential biomarker for predicting prognosis in AML patients.
- Targeting ferroptosis pathways could offer novel treatment options for refractory AML.
