Yang Y, Xu C H, Wang N, Fan J T, Yang D D, Niu M M, Shen L, Wang H
Haihe Laboratory of Cell Ecosystem, Tianjin Medical University, Tianjin 300070, China.
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China.
Zhonghua Xue Ye Xue Za Zhi. 2025 May 14;46(5):460-467. doi: 10.3760/cma.j.cn121090-20250114-00028.
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. 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. 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.
研究维奈托克在急性髓系白血病（AML）中的抗白血病作用及耐药机制。从Beat AML数据库下载接受维奈托克药物敏感性测试的AML患者的基因组、转录组和临床数据。对这些数据与维奈托克敏感性结果进行相关性分析。从转录组数据中鉴定出与维奈托克敏感性相关的差异表达基因（DEG），随后使用GEO数据库转录组结果和体外实验（包括蛋白质印迹法）进行验证。采用功能富集分析（KEGG和GSEA）、转录因子富集分析（KnockTF）以及公共数据库的数据，进一步研究影响药物敏感性的关键基因和通路。在对Beat AML队列进行筛选后，纳入52例有体外维奈托克敏感性结果的患者样本数据进行分析。与FLT3野生型患者相比，FLT3突变患者对维奈托克表现出更高的敏感性。临床信息与药物敏感性数据之间的相关性分析表明，外周血肿瘤负荷较高与对维奈托克的敏感性增加相关。转录组分析和体外实验证实，维奈托克抑制FLT3相关信号通路，包括FLT3表达下调及其下游靶点AKT和STAT5的磷酸化减少。KEGG通路和KnockTF转录因子富集分析表明，维奈托克耐药与FOXM1和STAT3转录活性增加有关。此外，FOXM1和STAT3的高表达与患者较短的总生存期相关。维奈托克可抑制FLT3相关信号通路的激活。STAT3和FOXM1转录因子的激活是导致AML中维奈托克耐药的潜在关键机制。
