Transcriptome-Wide Analysis of RNA N⁶-Methyladenosine Modification in Adriamycin-Resistant Acute Myeloid Leukemia...

Acute myeloid leukemia (AML) is one of the most aggressive hematopoietic malignancies. Patients still suffer from refractory/relapsed disease after anthracycline-based therapy, which leads to a poor prognosis. N⁶-Methyladenosine (m⁶A) is the most abundant post-transcriptional modification in eukaryotes, the imbalance of which is reported to be associated with various pathological processes, including drug resistance. However, the relationship between m⁶A modification and drug resistance has not been well defined in AML. In this study, we analyzed the sequencing data of HL60 and its Adriamycin-resistant cell line HL60/ADR. We found a total of 40,550 m⁶A-methylated peaks, representing 15,640 genes in HL60, and 38,834 m⁶A-methylated peaks, representing 15,285 genes in HL60/ADR. KEGG pathway analysis showed that pathways were enriched in the FoxO signaling pathway, p53 signaling pathway, and Notch signaling pathway. MeRIP-seq results showed that the fold enrichment of the global m⁶A level in HL60/ADR was higher than that in HL60, and dot blot assay results indicated that the global m⁶A level was elevated in HL60/ADR cells compared with that in HL60 cells. Further analysis revealed that the expression level of METTL3 was elevated in HL60/ADR cells compared with that in HL60 cells. After a combined treatment of STM2457 (an inhibitor of METTL3) and Adriamycin, the proliferation of HL60/ADR was inhibited. Thus, we hypothesized that the abnormality of m⁶A modification played an important role in Adriamycin-resistant AML.