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

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