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

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 activates the transcription of endogenous retroviruses (ERV), which can induce immune response by acting as cellular double-stranded RNAs. Here, we employ an image-based screening system to identify dsRNA-binding factors that mediate the downstream effect of ERV induction. 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 and TINCR expressions exhibited poor response to the HMA therapy. Our study reveals that decitabine-mediated cell death is a consequence of complex interactions among different dsRNA binding proteins for access to their common dsRNA targets. ncRNA and total RNA profiles of WT HCT116 and Staufen1-deficient HCT116.