Zhongguo shi yan xue ye xue za zhi · 2025
[The Epigenetic Regulation of Decitabine Resistance in TP53 -Mutated Myelodysplastic Syndromes: Integrated Analysis Based on RNA-seq and Methylomics].
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Zhang Lan, Ren Yu-Ye, Chen Wei, Hu Wen-Ya, Zhao Chen-Xi, Su Li-Ping
Аннотация
OBJECTIVE: To investigate the effects of TP53 genetic status (wild-type/mutated/null) on the drug resistance of decitabine (DAC) in myelodysplastic syndromes (MDS) and identify key resistance-associated genes.
METHODS: Two myeloid cell lines with distinct TP53 status (M-07e: wild-type; SKM-1: mutated;) were treated with gradient DAC concentrations (0-10 μmol/L) for 0-72 h. Cell viability was detected by CCK-8 assay. RNA-Seq transcriptomics, and methylation profiling were integrated to analyze differentially expressed genes.
RESULTS: Decitabine (DAC) treatment induced time- and dose-dependent inhibition of cell viability in CCK-8 assays, with SKM-1 cells exhibiting the highest resistance (IC50=5 μmol/L vs M-07e=0.5 μmol/L, P < 0.01). Transcriptomic analysis revealed 662 upregulated and 452 downregulated genes in DAC-treated M-07e cells, while SKM-1 cells showed 515 upregulated and 73 downregulated genes. By proteomic profiling, 117 upregulated and 136 downregulated proteins were identified in M-07e cells, while 91 upregulated and 46 downregulated proteins were identified in SKM-1 cells following DAC exposure. Through integrated analysis of upregulated genes and proteins expression profiles, 181 candidate genes were screened out, while methylation studies identified 884 hypomethylated genes with high-sensitivity loci and CpG density. Notably, 31 genes overlapped between these datasets, and functional annotation indicated these drug-resistance-associated genes are primarily involved in positive regulation of cell differentiation, negative regulation of binding processes, and negative regulation of cellular component organization.
CONCLUSION: TP53 mutations drive DAC resistance via epigenetic reprogramming. Targeting these genes may improve outcomes in TP53 -mutated MDS.
METHODS: Two myeloid cell lines with distinct TP53 status (M-07e: wild-type; SKM-1: mutated;) were treated with gradient DAC concentrations (0-10 μmol/L) for 0-72 h. Cell viability was detected by CCK-8 assay. RNA-Seq transcriptomics, and methylation profiling were integrated to analyze differentially expressed genes.
RESULTS: Decitabine (DAC) treatment induced time- and dose-dependent inhibition of cell viability in CCK-8 assays, with SKM-1 cells exhibiting the highest resistance (IC50=5 μmol/L vs M-07e=0.5 μmol/L, P < 0.01). Transcriptomic analysis revealed 662 upregulated and 452 downregulated genes in DAC-treated M-07e cells, while SKM-1 cells showed 515 upregulated and 73 downregulated genes. By proteomic profiling, 117 upregulated and 136 downregulated proteins were identified in M-07e cells, while 91 upregulated and 46 downregulated proteins were identified in SKM-1 cells following DAC exposure. Through integrated analysis of upregulated genes and proteins expression profiles, 181 candidate genes were screened out, while methylation studies identified 884 hypomethylated genes with high-sensitivity loci and CpG density. Notably, 31 genes overlapped between these datasets, and functional annotation indicated these drug-resistance-associated genes are primarily involved in positive regulation of cell differentiation, negative regulation of binding processes, and negative regulation of cellular component organization.
CONCLUSION: TP53 mutations drive DAC resistance via epigenetic reprogramming. Targeting these genes may improve outcomes in TP53 -mutated MDS.