Hypomethylating agents increase L1 retroelement expression without inducing novel insertions in myeloid malignancies

Retroelements in the human genome are silenced via multiple mechanisms, including DNA methylation, to prevent their potential mutagenic effect. Retroelement activity, demonstrated by their expression and somatic retrotransposition events, was shown to be deregulated in multiple tumors but not yet in leukemia. We hypothesized that treatment with hypomethylating agents, commonly used in myelodysplastic syndromes and acute myeloid leukemia, could lead to increased retroelement activity and somatic retrotranspositions, thus contributing to disease progression. To address this hypothesis, we induced the expression of ORF1p protein with hypomethylating agents in DAMI and HL-60 myeloid cell lines. To study whether long-term hypomethylating agent therapy induces somatic retrotranspositions, we analyzed (i) both cell lines treated for 4 weeks, and (ii) sequential samples from 17 patients with myelodysplastic syndrome treated with hypomethylating agents. Using a sensitive next-generation sequencing (NGS)-based method, no retroelement events were identified. To conclude, we show that although hypomethylating agents induce the expression of LINE-1-encoded proteins in myeloid cell lines, de novo somatic retrotransposition events do not arise during the long-term exposure to these agents.