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

作　　者：Fei Yan Aref AI-Kali Zijie Zhang Jun Liu Jiuxia Pang Na Zhao Chuan He Mark R. Litzow Shujun Liu Fei Yan;Aref AI-Kali;Zijie Zhang;Jun Liu;Jiuxia Pang;Na Zhao;Chuan He;Mark R. Litzow;Shujun Liu(The Flormel Institute, University of Minnesota, Austin, MN 55912, USA;Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA;Department of Chemistry,Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medicai institute, University of Chicago, Chicago, IL 60637, USA)

机构地区：[1]The Flormel Institute, University of Minnesota, Austin, MN 55912, USA [2]Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA [3]Department of Chemistry,Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medicai institute, University of Chicago, Chicago, IL 60637, USA

出　　处：《Cell Research》2018年第11期1062-1076,共15页细胞研究（英文版）

摘　　要：N^6-methyladenosine （m^6A） on mRNAs is critical for various biological processes, yet whether m^6A regulates drug resistance remains unknown. Here we show that developing resistant phenotypes during tyrosine kinase inhibitor （TKI） therapy depends on m^6A reduction resulting from Fro overexpression in leukemia cells. This deregulated FTO-m^6A axis pre-exists in naTve cell populations that are genetically homogeneous and is inducible/reversible in response to TKI treatment. Cells with mRNA m^6A hypomethylation and FTO upregulation demonstrate more TKI tolerance and higher growth rates in mice. Either genetic or pharmacological restoration of m^6A methylation through FTO deactivation renders resistant cells sensitive to TKIs. Mechanistically, the FTO- dependent m^6A demethylation enhances mRNA stability of proliferation/survival transcripts bearing m^6A and subsequently leads to increased protein synthesis. Our findings identify a novel function for the m^6A methylation in regulating cell fate decision and demonstrate that dynamic m^6A methylome is an additional epigenetic driver of reversible TKI-tolerance state, providing a mechanistic paradigm for drug resistance in cancer.

关 键 词：酷氨酸 调整 MRNA 蛋白质合成 生物过程 调查结果 FTO 机械学 

分 类 号：Q517.03[生物学—生物化学] Q78