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In myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sublines were evaluated comparatively with transcriptomic and methylomic analyses. Expression profiling and genome-wide methylation microarray showed downregulation of <i>PTEN</i> associated with DNA hypermethylation in P39 cell lines resistant to azacitidine and decitabine. This pattern of <i>PTEN</i> dysregulation was also confirmed in a cohort of patients failing treatment with HMA. DNA hypomethylation of <i>MDM2</i> was detected with downregulation of <i>MDM2</i> in HMA resistant cell lines. Long-read sequencing revealed significant RNA hypomethylation of <i>MDM2</i> resulting in alternative splicing and production of a truncated <i>MDM2</i> transcript in azacitidine-resistant P39 cells. The expression of this <i>MDM2</i> truncated transcript was also significantly increased in HMA-resistant patients compared with HMA-responsive patients. In conclusion, epigenetic and epi-transcriptomic dysregulation of <i>PTEN</i> and <i>MDM2</i> were associated with resistance to hypomethylating agents.