The RNA N⁶-Methyladenosine MethylomeCoordinates Long Non-Coding RNAs to MediateCancer Drug Resistance by Activating...

Long non-coding RNAs (lncRNAs) and RNA N6-methyladenosine (m⁶A) have been linked to leukemia drug resistance. However, whether and how lncRNAs and m⁶A coordinately regulate resistance remain elusive. Here, we show that many differentially expressed lncRNAs enrich m⁶A, and more lncRNAs tend to have higher m⁶A content in CML cells resistant to tyrosine kinase inhibitors (TKIs). We demonstrate broad clinical relevance of our findings, showing that upregulation of top-ranked lncRNAs (e.g., SENCR, PROX1-AS1, LN892) in TKI resistant cell lines occurs in CML patients at the diagnostic stage, blast crisis phase or not-responding to TKIs compared to chronic phase or TKI responders, respectively. Higher lncRNAs predict drug resistance and shorter survival duration. Knockdown of SENCR, PROX1-AS1 or LN892 restores TKI sensitivity. Mechanistically, upregulation of PROX1-AS1, SENCR and LN892 results from FTO-dependent m⁶A hypomethylation that stabilizes lncRNA transcripts, and empowers resistant cell growth through overexpression of PI3K signaling mediators (e.g., ITGA2, F2R, COL6A1). Treatment with PI3K inhibitor alpelisib eradicates resistant cells in vitro and in vivo with prolonged survival of leukemic mice through downregulation of F2R, ITGA2 and COL6A1. Thus, the lncRNA-m⁶A-PI3K cascade represents a new non-genetic predictor for drug resistance and poorer prognosis in cancer, and a pan-cancer mechanism underlying TKI resistance.