Abstract
Purpose
The study aims to investigate the impact of m6A modulators on drug resistance and the immune microenvironment in acute myeloid leukemia (AML). The emergence of drug resistance is a significant factor that contributes to relapse and refractory AML, leading to a poor prognosis.
Methods
The AML transcriptome data were retrieved from the TCGA database. The “oncoPredict” R package was utilized to assess the sensitivity of each sample to cytarabine (Ara-C) and classify them into distinct groups. Differential expression analysis was performed to identify m6A modulators differentially expressed between the two groups. Select Random Forest (RF) to build a predictive model. Model performance was evaluated using calibration curve, clinical decision curve, and clinical impact curve. The impacts of METTL3 on Ara-C sensitivity and immune microenvironment in AML were examined using GO, KEGG, CIBERSORT, and GSEA analyses.
Results
Seventeen out of 26 m6A modulators exhibited differential expression between the Ara-C-sensitive and resistant groups, with a high degree of correlation. We selected the 5 genes with the highest scores in the RF model to build a reliable and accurate prediction model. METTL3 plays a vital role in m6A modification, and further analysis shows its impact on the sensitivity of AML cells to Ara-C through its interaction with 7 types of immune-infiltrating cells and autophagy.
Conclusion
This study utilizes m6A modulators to develop a prediction model for the sensitivity of AML patients to Ara-C, which can assist in treating AML drug resistance by targeting mRNA methylation.
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Data availability
All the data used in this study are available upon request to the corresponding author.
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Acknowledgements
The authors would like to thank CJ, ZL, and ZLX for their help with the research.
Funding
This work was supported by the In-Hospital Fund of the First Hospital of Lanzhou University (interdisciplinary project) [No. ldyyyn2020-89].
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YJC and LLL designed the experiments, performed data collection and analysis, and wrote the manuscript. LJL, ZSL, and WS performed data collection and analysis. CJ advised on experimental design and data interpretation. ZL provides funding support for experiments. ZL and ZLX advised on experimental design, assisted in writing the manuscript, and supervised the study.
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Yang, J., Li, L., Cheng, J. et al. The m6A modulator-mediated cytarabine sensitivity and immune cell infiltration signature in acute myeloid leukemia. J Cancer Res Clin Oncol 149, 11457–11469 (2023). https://doi.org/10.1007/s00432-023-05029-x
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DOI: https://doi.org/10.1007/s00432-023-05029-x