Epigenetic Silencing of PTEN and Epi‐Transcriptional Silencing of MDM2 Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents

Abstract

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 PTEN associated with DNA hypermethylation in P39 cell lines resistant to azacitidine and decitabine. This pattern of PTEN dysregulation was also confirmed in a cohort of patients failing treatment with HMA. DNA hypomethylation of MDM2 was detected with downregulation of MDM2 in HMA resistant cell lines. Long‐read sequencing revealed significant RNA hypomethylation of MDM2 resulting in alternative splicing and production of a truncated MDM2 transcript in aza-citidine‐resistant P39 cells. The expression of this MDM2 truncated transcript was also significantly increased in HMA‐resistant patients compared with HMA‐responsive patients. In conclusion, epigenetic and epi‐transcriptomic dysregulation of PTEN and MDM2 were associated with resistance to hypomethylating agents.