Liu Shujun
The Metrohealth System, Case Western Reser.
Res Sq. 2024 Dec 18:rs.3.rs-5663230. doi: 10.21203/rs.3.rs-5663230/v1.
Long non-coding RNAs (lncRNAs) and RNA N6-methyladenosine (mA) have been linked to leukemia drug resistance. However, whether and how lncRNAs and mA coordinately regulate resistance remain elusive. Here, we show that many differentially expressed lncRNAs enrich mA, and more lncRNAs tend to have higher mA 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 mA 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 and with prolonged survival of leukemic mice through downregulation of F2R, ITGA2 and COL6A1. Thus, the lncRNA-mA-PI3K cascade represents a new non-genetic predictor for drug resistance and poorer prognosis in cancer, and a pan-cancer mechanism underlying TKI resistance.
长链非编码RNA（lncRNAs）和RNA N6-甲基腺苷（m⁶A）与白血病耐药性有关。然而，lncRNAs和m⁶A是否以及如何协同调节耐药性仍不清楚。在这里，我们表明许多差异表达的lncRNAs富集m⁶A，并且在对酪氨酸激酶抑制剂（TKIs）耐药的慢性粒细胞白血病（CML）细胞中，更多的lncRNAs往往具有更高的m⁶A含量。我们证明了我们的发现具有广泛的临床相关性，表明在TKI耐药细胞系中排名靠前的lncRNAs（如SENCR、PROX1-AS1、LN892）的上调分别发生在CML患者的诊断阶段、急变期或与慢性期或TKI反应者相比对TKI无反应的阶段。较高的lncRNAs预示着耐药性和较短的生存期。敲低SENCR、PROX1-AS1或LN892可恢复TKI敏感性。从机制上讲，PROX1-AS1、SENCR和LN892的上调是由FTO依赖的m⁶A低甲基化导致的，这种低甲基化使lncRNA转录本稳定，并通过PI3K信号介质（如ITGA2、F2R、COL6A1）的过表达促进耐药细胞生长。用PI3K抑制剂阿培利司治疗可根除耐药细胞，并通过下调F2R、ITGA2和COL6A1延长白血病小鼠的生存期。因此，lncRNA-m⁶A-PI3K级联代表了一种新的癌症耐药性和较差预后的非遗传预测指标，以及TKI耐药的泛癌机制。
