The Epigenetic Regulation of Decitabine Resistance in TP53-Mutated Myelodysplastic Syndromes:Integrated Analysis Based on RNA-seq and Methylomics
10.19746/j.cnki.issn1009-2137.2025.06.019
- VernacularTitle:TP53突变型骨髓增生异常综合征对地西他滨耐药的表观遗传调控:基于RNA-seq与甲基化组学的整合分析
- Author:
Lan ZHANG
1
;
Yu-Ye REN
;
Wei CHEN
;
Wen-Ya HU
;
Chen-Xi ZHAO
;
Li-Ping SU
Author Information
1. 山西医科大学第一医院血液科,山西太原 030001
- Publication Type:Journal Article
- Keywords:
TP53;
myelodysplastic syndromes;
decitabine;
drug resistance;
epigenetic regulation
- From:
Journal of Experimental Hematology
2025;33(6):1681-1687
- CountryChina
- Language:Chinese
-
Abstract:
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.
