Bioinformatic analysis of venetoclax sensitivity and resistance mechanisms in acute myeloid leukemia
10.3760/cma.j.cn121090-20250114-00028
- VernacularTitle:基于生物信息学分析探究维奈克拉对急性髓系白血病的治疗敏感性及耐药机制
- Author:
Yang YANG
1
;
Chenghua XU
;
Ning WANG
;
Jinting FAN
;
Dandan YANG
;
Mingming NIU
;
Long SHEN
;
Hong WANG
Author Information
1. 天津医科大学，细胞生态海河实验室，天津 300070
- Publication Type:Journal Article
- Keywords:
Venetoclax;
Acute myeloid leukemia;
Bioinformatics analysis;
Drug resistance
- From:
Chinese Journal of Hematology
2025;46(5):460-467
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the anti-leukemic effects and resistance mechanisms of venetoclax in acute myeloid leukemia (AML). Genomic, transcriptomic, and clinical data from AML patients who underwent venetoclax drug sensitivity testing were downloaded from the Beat AML database. Correlation analysis was performed between these data and venetoclax sensitivity outcomes. Differentially expressed genes (DEGs) associated with venetoclax sensitivity were identified from transcriptomic data and subsequently validated using GEO database transcriptomic results and in vitro experiments (including Western blot). Functional enrichment analyses (KEGG and GSEA), transcription factor enrichment analysis (KnockTF), and data from public databases were employed to further investigate key genes and pathways influencing drug sensitivity.Results:After filtering the Beat AML cohort, data from 52 patient samples with available in vitro venetoclax sensitivity results were included for analysis. Patients with FLT3 mutations exhibited greater sensitivity to venetoclax compared to those with FLT3 wild-type. Correlation analysis between clinical information and drug sensitivity data indicated that higher peripheral blood tumor burden was associated with increased sensitivity to venetoclax. Transcriptomic analysis and in vitro experiments confirmed that venetoclax inhibits the FLT3-related signaling pathway, including downregulation of FLT3 expression and reduced phosphorylation of its downstream targets AKT and STAT5. KEGG pathway and KnockTF transcription factor enrichment analyses indicated that venetoclax resistance was associated with increased transcriptional activity of FOXM1 and STAT3. Moreover, high expression of FOXM1 and STAT3 correlated with shorter overall survival in patients.Conclusion:Venetoclax can inhibit the activation of FLT3-related signaling pathways. The activation of STAT3 and FOXM1 transcription factors is a potential key mechanism contributing to venetoclax resistance in AML.
