Double-stranded RNA induction asa potential dynamic biomarkerfor DNA-demethylating agents

Minjeong Kang, Raisa Kharbash, Ja Min Byun, Jaemin Jeon, Ahsan Ausaf Ali, Doyeong Ku, Jimin Yoon, Yongsuk Ku, Jooyeon Sohn, Seung Jae V. Lee, Dong Yeop Shin, Youngil Koh, Sung Soo Yoon, Junshik Hong, Yoosik Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Hypomethylating agents (HMAs), such as azacitidine and decitabine, induce cancer cell death by demethylating DNAs to promote the expression of tumor-suppressor genes. HMAs also reactivate the transcription of endogenous double-stranded RNAs (dsRNAs) that trigger the innate immune response and subsequent apoptosis via viral mimicry. However, the expression patterns of endogenous dsRNAs and their relevance in the efficacy of HMAs remain largely uninvestigated. Here, we employ amidine-conjugated spiropyran (Am-SP) to examine the dynamic expression pattern of total dsRNAs regulated by HMAs. By analyzing the bone-marrow aspirates of myelodysplastic syndrome or acute myeloid leukemia patients who received the HMAs, we find a dramatic increase in total dsRNA levels upon treatment only in patients who later benefited from the therapy. We further apply our approach in solid tumor cell lines and show that the degree of dsRNA induction correlates with the effectiveness of decitabine in most cases. Notably, when dsRNA induction is accompanied by increased expression of nc886 RNA, decitabine becomes ineffective. Collectively, our study establishes the potential application of monitoring the total dsRNA levels by a small molecule as an analytical method and a dynamic marker to predict the clinical outcome of the HMA therapy.

Original languageEnglish
Pages (from-to)370-383
Number of pages14
JournalMolecular Therapy - Nucleic Acids
Volume29
DOIs
StatePublished - 13 Sep 2022

Keywords

  • MT: Noncoding RNAs
  • PKR
  • double-stranded RNAs
  • dynamic biomarker
  • hypomethylating agents
  • innate immune response
  • nc886
  • spiropyran

Fingerprint

Dive into the research topics of 'Double-stranded RNA induction asa potential dynamic biomarkerfor DNA-demethylating agents'. Together they form a unique fingerprint.

Cite this