Zhou Yanqun, Zhang Xiongfeng, Yin Shangjin, Yao Yuhong, Chen Tao, Huang Liming, Liu Zenghui
The Second Clinical Medical School of Guizhou University of Chinese Medicine, No. 83, Feishan Street, Yunyan District, Guiyang, 550003, Guizhou Province, People's Republic of China.
Department of Hematology, The Second Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang, People's Republic of China.
Inflamm Res. 2025 Apr 30;74(1):77. doi: 10.1007/s00011-025-02038-z.
Observational studies suggest that a history of inflammatory bowel disease (IBD) is associated with the onset of acute myeloid leukemia (AML), often attributed to drug use. However, these findings are inconsistent. This study aimed to assess the causal relationship between IBD and AML, identify shared pathogenesis, and discover diagnostic and prognostic markers and potential therapeutic drugs.
Two-sample Mendelian randomization (MR) was employed to analyze genetic associations between IBD [ulcerative colitis (UC) and Crohn's disease (CD)] and AML. Transcriptomic data from gene expression omnibus (GEO) identified differentially expressed genes (DEGs) in UC, AML, and controls. Weighted Gene Co-expression Network Analysis (WGCNA) and enrichment analyses [Gene Multiple Association Network Integration Algorithm (GeneMANIA), Kyoto Encyclopedia of Genes and Genomes (KEGG), Ractom pathway] and Gene Ontology (GO) explored shared genetic pathways. Receiver Operating Characteristic (ROC) curve and survival analyses screened diagnostic and prognostic markers. Cibersort and GSVA were employed to analyze the proportion of immune cells in UC and AML datasets, as well as to assess the association of specific genes with immune infiltration. The Drug Signatures Database (DSigDB) and Autodock molecular docking identified potential therapeutic small molecules.
MR analysis revealed a causal association between UC and the onset of AML. Differential expression and WGCNA analyses identified 23 co-driver genes regulated by Signal Transducer and Activator of Transcription 3 (STAT3) and Activating Transcription Factor 4 (AFT4), enriched in immune, inflammatory, and cell proliferation pathways. Tissue Inhibitor of Metalloproteinases 1 (TIMP1) and F2R-Like Trypsin Receptor 1 (F2RL1) were identified as practical diagnostic and prognostic markers for AML, with high TIMP1 and low F2RL1 expression promoting an immunosuppressive and inflammatory tumor microenvironment. Quercetin was identified as a promising candidate for UC-associated AML.
UC is a risk factor for AML pathogenesis. TIMP1 and F2RL1 are diagnostic and prognostic markers for UC-associated AML, potentially facilitating AML development through sustained inflammation and an immunosuppressive tumor microenvironment. Quercetin, a potential TIMP1 and F2RL1 inhibitor, may mitigate UC-AML transformation, providing insights into UC management, AML monitoring, and preventive therapy development.
观察性研究表明，炎症性肠病（IBD）病史与急性髓系白血病（AML）的发病相关，这通常归因于药物使用。然而，这些发现并不一致。本研究旨在评估IBD与AML之间的因果关系，确定共同的发病机制，发现诊断和预后标志物以及潜在的治疗药物。
采用两样本孟德尔随机化（MR）分析IBD[溃疡性结肠炎（UC）和克罗恩病（CD）]与AML之间的基因关联。来自基因表达综合数据库（GEO）的转录组数据确定了UC、AML和对照中的差异表达基因（DEG）。加权基因共表达网络分析（WGCNA）和富集分析[基因多重关联网络整合算法（GeneMANIA）、京都基因与基因组百科全书（KEGG）、Ractom通路]以及基因本体论（GO）探索了共同的遗传途径。受试者工作特征（ROC）曲线和生存分析筛选了诊断和预后标志物。采用Cibersort和GSVA分析UC和AML数据集中免疫细胞的比例，以及评估特定基因与免疫浸润的关联。药物特征数据库（DSigDB）和自动对接分子对接确定了潜在的治疗性小分子。
MR分析揭示了UC与AML发病之间的因果关系。差异表达和WGCNA分析确定了23个由信号转导和转录激活因子3（STAT3）和激活转录因子4（AFT4）调控的共同驱动基因，这些基因富集于免疫、炎症和细胞增殖途径。金属蛋白酶组织抑制剂1（TIMP1）和F2R样胰蛋白酶受体1（F2RL1）被确定为AML的实用诊断和预后标志物，高TIMP1和低F2RL1表达促进免疫抑制和炎症性肿瘤微环境。槲皮素被确定为UC相关AML的一个有前景的候选药物。
UC是AML发病机制的一个危险因素。TIMP-1和F2RL1是UC相关AML的诊断和预后标志物，可能通过持续炎症和免疫抑制性肿瘤微环境促进AML的发展。槲皮素作为一种潜在的TIMP1和F2RL1抑制剂，可能减轻UC向AML的转化，为UC的管理、AML的监测和预防性治疗的发展提供见解。
