Mobile retroelements induced by hypomethylating agents are restricted to transpose in myeloid malignancies

Abstract

Retroelements (RE) present in the human genome are silenced via multiple mechanisms, including DNA methylation, to prevent their potentially mutagenic effect. RE activity, demonstrated by their expression and somatic retrotransposition events, is deregulated in multiple tumor types but not in leukemia. We hypothesized that treatment with hypomethylating agents (HMA), commonly used in myelodysplastic syndromes and acute myeloid leukemia, could lead to increased RE activity and somatic retrotranspositions, and contribute to disease progression. We induced expression of ORF1p protein encoded by long interspersed nuclear element-1 (L1) after 72h treatment with HMA in DAMI and HL-60 cell lines. ORF1p was predominantly localized in the cytoplasm, as evidenced by fluorescent microscopy of the DAMI cell line. To study whether long-term HMA therapy may induce somatic retrotranspositions, we (i) treated both cell lines for four weeks, (ii) analyzed a cohort of 17 MDS patients before and on treatment with HMA. Using a previously established sensitive NGS-based method, no RE events were identified. To conclude, we show that although HMA induces the expression of L1-encoded proteins in tumor myeloid cell lines, de novo somatic retrotransposition events do not arise during the long-term treatment of MDS patients and myeloid cell lines with these agents.