Abstract
OBJECTIVE: Acute myeloid leukemia (AML) is a malignant blood disease with a poor prognosis. With the development of targeted therapies, many refractory/relapsed or unfit AML patients have achieved better survival rates. However, primary or acquired resistance frequently occurs, and some targets become unavailable. This study aimed to identify and verify novel targets for AML using Mendelian Randomization (MR) analysis. METHOD: The association between plasma protein quantitative trait loci (pQTL), expression quantitative trait loci (eQTL), and AML was examined via MR. Bayesian co-localization analysis was used to detect common segments of TCL1A and AML. Bioinformatics technology was used to explore the relationship between TCL1A and AML, and quantitative real-time PCR (RT-qPCR) analysis was used to detect the expression of TCL1A in various cell lines. Furthermore, high-throughput virtual screening (HTVS) and molecular dynamics (MD) simulation was used to identify potential TCL1A inhibitors. Further verification was carried out by AML cell experiments. RESULTS: Our study found a strong association between plasma TCL1A protein levels and AML (OR: 1.66; 95% CI: 1.46–1.88), and rs78986913 was the same variant in both TCL1A and AML. High TCL1A expression was associated with low overall survival rates in AML patients (P < 0.001), especially in the FAB M0 and M2 subgroups. Additionally, TCL1A was abnormally highly expressed in many AML cell lines (including MOLM-13, MV4-11, THP-1) compared to normal bone marrow stromal cells (HS-5) and other solid tumor cells. We also identified 19 small molecules, finding that Bletilloside A (id number: 2292159-89-6) is one of the most fitting small molecules for the TCL1A protein pocket. MD simulation confirmed the good stability of the Bletilloside A-TCL1A complex. And Bletilloside A could inhibit the proliferation of AML by inhibiting TCL1A. CONCLUSION: There is a causal relationship between TCL1A and AML. The expression level of TCL1A deserves further monitoring in clinical settings, and the benefits of targeting TCL1A should be further validated. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-025-15438-5.