Non-canonical immune response to inhibition of DNA methylation via stabilization of dsRNAs from endogenous retroviruses

Abstract

5-Aza-2'-deoxycytidine, also known as decitabine, is a DNA hypomethylating agent (HMA) used to treat acute myeloid leukemia (AML) and pre-leukemic disorder myelodysplastic syndrome (MDS). Decitabine induces cell death by activating transcription of endogenous retroviral elements (ERVs). When transcribed, ERV RNAs can adopt double-stranded secondary structure and activate melanoma differentiation-associated protein 5 (MDA5), a member of the innate immune response proteins that recognize viral double-stranded RNAs (dsRNAs). Here, we employ an image-based RNAi screening system to identify dsRNA-binding factors that affect cellular response to ERV induction by decitabine. We find that Staufen1 (Stau1) knockdown decreases the interferon signature and rescues decitabine-mediated cell death. Our subsequent analyses reveal that Stau1 directly binds to ERV RNAs and stabilizes the RNAs together with a long noncoding RNA, TINCR. Analysis of a clinical patient cohort further supports that MDS and AML patients with low Stau1 expressions exhibited poor response to HMA. Our study reveals that decitabine-mediated cell death is a consequence of complex interactions among different dsRNA binding proteins for access to common dsRNA targets.