Volume 28, No 11, Nov 2018
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 28 Issue 11, November 2018: 1062-1076 | Open Access
ORIGINAL ARTICLES
A dynamic N6-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors
Fei Yan 1 , Aref Al-Kali 2 , Zijie Zhang 3 , Jun Liu 3 , Jiuxia Pang 1 , Na Zhao 1 , Chuan He 3 , Mark R. Litzow 2 and Shujun Liu 1
1 The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; 2Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA and 3Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA
Correspondence: Correspondence: Chuan He (chuanhe@uchicago.edu) or Mark R. Litzow (litzow.mark@mayo.edu) or Shujun Liu (sliu@umn.edu)These authors contributed equally: Fei Yan, Aref Al-Kali, Zijie Zhang
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.
https://doi.org/10.1038/s41422-018-0097-4
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