The Therapeutic Response of Myelodsyplastic Syndromes to Azacytidine is Independent of Endogenous Retroelement Modulation

Hypomethylating agents (HMA) such as azacytidine and decitabine are the mainstay of treatment for higher risk myelodysplastic syndromes (MDS) and are also used to treat older, unfit patients with acute myeloid leukemia (AML). Being cytidine analogues, both azacytidine and decitabine are incorporated into DNA of highly proliferating cells leading to genome-wide decrease of methylation levels (Stresemann & Lyko., 2008; Gnyszka et al., 2013), whereas azacytidine is additionally incorporated into RNA molecules. Although several putative modes of action have been suggested for HMA, the precise mechanism underlying treatment success or failure remains incompletely understood. One possible mechanism of HMA action is through ‘viral mimicry’ of transcriptionally repressed endogenous retroelements (EREs), which is thought to trigger innate immune pathways. EREs comprise nearly half of the human genome and their transcriptional activity is repressed by diverse mechanisms including DNA methylation. According to the ‘viral mimicry’ hypothesis, HMA induce unphysiological levels of ERE transcription in transformed cells, which in turn generated nucleic acid species, such as double-stranded RNAs from complementary ERE transcripts, activating innate immune sensors. Although support and a mechanistic basis for this hypothesis is provided from a number of in vitro studies, in vivo evidence from the clinical use of HMA is currently lacking.