The role of METTL14 in the progression of chronic myeloid leukemia
Objectives Chronic myeloid leukemia (CML), a clonal malignant disease arising from the BCR-ABL fusion gene, presents significant therapeutic challenges, particularly in chemotherapy resistance. The role of METTL14, a key m6A methyltransferase, is implicated in cancer biology, but its role in CML rem...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2025-12-01
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| Series: | Hematology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/16078454.2025.2535819 |
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| Summary: | Objectives Chronic myeloid leukemia (CML), a clonal malignant disease arising from the BCR-ABL fusion gene, presents significant therapeutic challenges, particularly in chemotherapy resistance. The role of METTL14, a key m6A methyltransferase, is implicated in cancer biology, but its role in CML remains unclear.Methods Peripheral blood mononuclear cells (PBMCs) and CML cell lines (K562 and K562/G01) were conducted in vitro studies. mRNA levels were quantified by quantitative PCR (qPCR), and protein expressions were assessed by Western Blotting. Cell viability and apoptosis were measured using the CCK-8 and flow cytometry, respectively. Drug resistance was evaluated by determining the half-maximal inhibitory concentration (IC50). m6A levels were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and modification sites were predicted by SRAMP and confirmed with a SELECT detection assay. Gene interactions were validated through luciferase assays.Results METTL14 expression was significantly elevated in imatinib-resistant CML patients (P=0.005) and K562/G01 cells (P=0.01), correlating with increased m6A modification levels (P=0.032). Overexpression of METTL14 enhanced m6A methylation, promoted cell proliferation, inhibited apoptosis, and increased imatinib resistance in CML cells. Conversely, METTL14 silencing reduced m6A levels, induced G0/G1 arrest, and enhanced apoptosis (P=0.01). Mechanistically, the luciferase assay results demonstrated that METTL14-mediated m6A modification at the A1001 site of Bcl-x mRNA facilitated HNRNPC-dependent splicing. Consequently, this modification results in shifting Bcl-xS to Bcl-xL and inactivating the BCL-2/BAX/Caspase-3 pathway.Conclusion METTL14-driven m6A modification regulates the splicing pattern of Bcl-x, and may facilitate the progression of CML. Keywords: CML, METTL14, N6-methyladenine, Bcl-x, Alternative splicing, resistance, imatinib, progression. |
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| ISSN: | 1607-8454 |