A dynamic N 6-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors

Fei Yan, Aref Al-Kali, Zijie Zhang, Jun Liu, Jiuxia Pang, Na Zhao, Chuan He, Mark R Litzow, Shujun Liu

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates drug resistance remains unknown. Here we show that developing resistant phenotypes during tyrosine kinase inhibitor (TKI) therapy depends on m6A reduction resulting from FTO overexpression in leukemia cells. This deregulated FTO-m6A axis pre-exists in naïve cell populations that are genetically homogeneous and is inducible/reversible in response to TKI treatment. Cells with mRNA m6A hypomethylation and FTO upregulation demonstrate more TKI tolerance and higher growth rates in mice. Either genetic or pharmacological restoration of m6A methylation through FTO deactivation renders resistant cells sensitive to TKIs. Mechanistically, the FTO-dependent m6A demethylation enhances mRNA stability of proliferation/survival transcripts bearing m6A and subsequently leads to increased protein synthesis. Our findings identify a novel function for the m6A methylation in regulating cell fate decision and demonstrate that dynamic m6A methylome is an additional epigenetic driver of reversible TKI-tolerance state, providing a mechanistic paradigm for drug resistance in cancer.

Original languageEnglish (US)
JournalCell Research
DOIs
StateAccepted/In press - Jan 1 2018

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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