A dynamic N⁶-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors.

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 TKI

SUBMITTER: Yan F 

PROVIDER: S-EPMC6218444 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature