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.
Highlights
Leukemia is an aggressive malignancy frequently associated with activating mutations of receptor tyrosine kinases (RTKs), including BCR/ABL, KIT and FLT3 etc.[1,2,3,4] Many tyrosine kinase inhibitors (TKIs) against these mutations have entered the clinic, but rapidly acquired resistance to TKIs represents a major hurdle to successful leukemia treatment
TKI-resistant cells survive and proliferate in the absence of targeted RTK signaling To understand TKI resistance mechanisms, a panel of four representative leukemia cell lines with activating mutations, BCR/ ABL (K562, KU812), KIT (Kasumi-1) and FLT3 (MV4-11), rendering them sensitive to kinase-targeted therapies were initially exposed to increasing concentrations of representative TKIs, nilotinib, 1The 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: Chuan He or Mark R
Exposure of these released cells to TKIs induced growth arrest supported by a dose-dependent decrease of EdU incorporation which was less pronounced compared to the parental cells (Fig. 1e)
Summary
Leukemia is an aggressive malignancy frequently associated with activating mutations of receptor tyrosine kinases (RTKs), including BCR/ABL, KIT and FLT3 etc.[1,2,3,4] Many tyrosine kinase inhibitors (TKIs) against these mutations have entered the clinic, but rapidly acquired resistance to TKIs represents a major hurdle to successful leukemia treatment. Many patients with resistance express exclusively native kinases (e.g., BCR/ABL) or have activated parallel pathways, involving overamplification of oncogenes (e.g., BCL-2, BCL-6, AXL and MET).[7,8,9,10] recent findings have linked acquired TKI resistance to cellular heterogeneity within tumors and dynamic variation in epigenome configurations.[11,12,13] It is postulated that the distinct epigenetic patterns in heterogeneous tumor cell populations could generate diversity in the expression of cell fate determination genes that can swiftly evolve through drug selection. Silencing of m6A methyltransferase (e.g., IME4, the yeast orthologue of METTL3) or knockdown of FTO changes m6A abundance, re-modeling gene expression profile and/or alternative splicing pattern of transcripts.[26,27,28] Despite recent works on roles of m6A in various biological processes,[23] whether and how m6A methylation regulates cell fate decisions under TKI selection remain unknown. Our discoveries establish the feasibility to target the FTO-m6A axis for prevention/eradication of acquired TKI resistance
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