The RNA N6-methyladenosine methylome coordinates long non-coding RNAs to mediate cancer drug resistance by activating PI3K signaling
Long non-coding RNAs (lncRNAs) and RNA N⁶-methyladenosine (m<sup>6</sup>A) have been linked to leukemia drug resistance. However, whether and how lncRNAs and m<sup>6</sup>A coordinately regulate resistance remain elusive. Here, we show that many differentially expressed lncRNAs enrich m<sup>6</sup>A, and more lncRNAs tend to have higher m<sup>6</sup>A content in CML cells resistant to tyrosine kinase inhibitors (TKIs). We demonstrate the broad clinical relevance of our findings, showing that upregulation of top-ranked lncRNAs (e.g., SENCR, PROX1-AS1, LINC00892) in TKI-resistant cell lines occurs in CML patients at the diagnostic stage, blast crisis phase, or not responding to TKIs compared to the chronic phase or TKI responders, respectively. Higher lncRNAs predict drug resistance and shorter survival duration. The knockdown of SENCR, PROX1-AS1, or LINC00892 restores TKI sensitivity. Mechanistically, upregulation of PROX1-AS1, SENCR, and LINC00892 results from FTO-dependent m<sup>6</sup>A 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-m<sup>6</sup>A-PI3K cascade represents a new non-genetic predictor for drug resistance and poorer prognosis in cancer, and a pan-cancer mechanism underlying TKI resistance.
Authors
- Sicheng Bian (ORCID: https://orcid.org/0000-0001-9527-2102)
- Aref Al‐Kali (ORCID: https://orcid.org/0000-0002-0824-3715)
- Gregor Hoermann (ORCID: https://orcid.org/0000-0002-7374-4380)
- Changli Zhou (ORCID: https://orcid.org/0000-0002-5984-4289)
- Yuchao Yang (ORCID: https://orcid.org/0000-0002-1558-266X)
- Yanhong Tan (ORCID: https://orcid.org/0000-0002-6257-8655)
- Huiqin Bian
- Wencke Walter (ORCID: https://orcid.org/0000-0002-5083-9838)
- Tao Cheng (ORCID: https://orcid.org/0000-0002-5925-2769)
- Rendong Yang (ORCID: https://orcid.org/0000-0002-9512-2240)
- Yun Ren (ORCID: https://orcid.org/0000-0003-2171-5913)
- Xiaonan Han (ORCID: https://orcid.org/0000-0001-5368-6489)
- Mark Robert Litzow (ORCID: https://orcid.org/0000-0002-9816-6302)
- Lingli Zhang (ORCID: https://orcid.org/0000-0003-3832-4046)
- Gang Huang (ORCID: https://orcid.org/0000-0002-5786-7110)
- Shujun Liu (ORCID: https://orcid.org/0000-0002-2605-8089)
- Hongwei Wang (ORCID: https://orcid.org/0000-0002-2902-591X)
- Jianhua Yu
- Jiuxia Pang
- Weiyong Guo (ORCID: https://orcid.org/0009-0005-4210-0258)
- William Tse
Institutions
- The University of Texas at San Antonio Health Science Center (US)
- Shanxi Medical University (CN)
- Munich Leukemia Laboratory (Germany) (DE)
- University of California, Irvine Medical Center (US)
- Mayo Clinic in Arizona (US)
- Second Hospital of Shanxi Medical University (CN)
- MetroHealth Medical Center (US)
- Case Western Reserve University (US)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1038/s41419-025-08045-6
- Citations
- 1
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- University of Minnesota
- Case Western Reserve University
- Shanxi Medical University
- National Cancer Institute