[The Epigenetic Regulation of Decitabine Resistance in TP53 -Mutated Myelodysplastic Syndromes: Integrated Analysis Based on RNA-seq and Methylomics].

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.