Comprehensive analysis of ferroptosis-related gene signatures as a potential therapeutic target for acute myeloid leukemia: A bioinformatics analysis and experimental verification

Zhiyuan Zheng; Xiaoying Hong; Xiaoxue Huang; Xiandong Jiang; He Jiang; Yingying Huang; Wei Wu; Yan Xue; Donghong Lin

doi:10.3389/fonc.2022.930654

Comprehensive analysis of ferroptosis-related gene signatures as a potential therapeutic target for acute myeloid leukemia: A bioinformatics analysis and experimental verification

Front Oncol. 2022 Aug 11:12:930654. doi: 10.3389/fonc.2022.930654. eCollection 2022.

Authors

Zhiyuan Zheng^{1

2}, Xiaoying Hong^{1

2}, Xiaoxue Huang³, Xiandong Jiang^{1

2}, He Jiang^{1

2}, Yingying Huang^{1

2}, Wei Wu^{1

2}, Yan Xue^{1

2}, Donghong Lin^{1

2}

Affiliations

¹ Medical Technology and Engineering College of Fujian Medical University, Fuzhou, China.
² Medical Technology Experimental Teaching Center of Fujian Medical University, Fuzhou, China.
³ Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, China.

Abstract

Background: Ferroptosis plays an important role in the development of acute myeloid leukemia (AML); however, the exact role of ferroptosis-related genes in the prognosis of AML patients is unclear.

Methods: RNA sequencing data and the clinicopathological characteristics of AML patients were obtained from The Cancer Genome Atlas database, and ferroptosis-related genes were obtained from the FerrDb database. Cox regression analysis and least absolute shrinkage and selection operator analysis were performed to identify ferroptosis-related gene signatures. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and single-sample gene set enrichment analysis (ssGSEA) were performed to explore the biological functions of the ferroptosis-related genes. Finally, ferroptosis of AML cells was induced by erastin and sulfasalazine to detect the changes in the expression of relevant prognostic genes and explore the underlying mechanisms using quantitative real-time polymerase chain reaction (qRT-PCR).

Results: Seven ferroptosis-related gene signatures (SOCS1, ACSF2, MYB, EIF2AK4, AIFM2, SLC7A11, and GPX4) were identified in the training group. Kaplan-Meier and Cox regression analyses confirmed that risk score was an independent prognostic predictor of AML in the training and validation groups (P<0.05). Further, functional enrichment analysis revealed that seven ferroptosis-related genes were associated with many immune-related biological processes. Most importantly, erastin and sulfasalazine can induce the ferroptosis of AML cells. Overall, SLC7A11 and the SLC7A11/xCT-GSH-GPX4 pathway may be the respective key gene and potential regulatory pathway in erastin- and sulfasalazine-induced ferroptosis of AML cells.

Conclusions: A novel signature involving seven ferroptosis-related genes that could accurately predict AML prognosis was identified. Further, the Food and Drug Administration-approved drug, sulfasalazine, was demonstrated for the first time to induce the ferroptosis of AML cells. SLC7A11 and the SLC7A11/xCT-GSH-GPX4 pathway may be the respective key gene and underlying mechanism in this process, ultimately providing new insights into the strategies for the development of new AML therapies.

Keywords: The Cancer Genome Atlas; acute myeloid leukemia; ferroptosis; gene signatures; prognosis; sulfasalazine.