The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
Division of Hematology, Mayo Clinic, Rochester, MN, 55905, USA.
Cell Res. 2018 Nov;28(11):1062-1076. doi: 10.1038/s41422-018-0097-4. Epub 2018 Oct 8.
N-methyladenosine (mA) on mRNAs is critical for various biological processes, yet whether mA regulates drug resistance remains unknown. Here we show that developing resistant phenotypes during tyrosine kinase inhibitor (TKI) therapy depends on mA reduction resulting from FTO overexpression in leukemia cells. This deregulated FTO-mA axis pre-exists in naïve cell populations that are genetically homogeneous and is inducible/reversible in response to TKI treatment. Cells with mRNA mA hypomethylation and FTO upregulation demonstrate more TKI tolerance and higher growth rates in mice. Either genetic or pharmacological restoration of mA methylation through FTO deactivation renders resistant cells sensitive to TKIs. Mechanistically, the FTO-dependent mA demethylation enhances mRNA stability of proliferation/survival transcripts bearing mA and subsequently leads to increased protein synthesis. Our findings identify a novel function for the mA methylation in regulating cell fate decision and demonstrate that dynamic mA methylome is an additional epigenetic driver of reversible TKI-tolerance state, providing a mechanistic paradigm for drug resistance in cancer.
N6-甲基腺苷（m6A）在信使 RNA 上对于各种生物学过程至关重要，但 m6A 是否调节药物耐药性尚不清楚。在这里，我们表明，在白血病细胞中，随着 FTO 过表达导致 m6A 减少，酪氨酸激酶抑制剂（TKI）治疗期间耐药表型的发展取决于 m6A 的减少。这种失调的 FTO-m6A 轴在遗传上同质的原始细胞群体中预先存在，并且可以响应 TKI 治疗而被诱导/逆转。m6A 低甲基化和 FTO 上调的 mRNA 显示出对 TKI 的更高耐受性和在小鼠中的更高增长率。通过 FTO 失活通过遗传或药理学恢复 m6A 甲基化可使耐药细胞对 TKI 敏感。从机制上讲，FTO 依赖性 m6A 去甲基化增强了具有 m6A 的增殖/存活转录本的 mRNA 稳定性，随后导致蛋白质合成增加。我们的发现确定了 m6A 甲基化在调节细胞命运决定中的新功能，并证明动态 m6A 甲基组是可逆 TKI 耐药状态的另一个表观遗传驱动因素，为癌症中的药物耐药性提供了一种机制范例。
