Comprehensive analysis of m 6 A methylome alterations after azacytidine plus venetoclax treatment for acute myeloid leukemia by nanopore sequencing

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N6 adenosine methylation (m 6 A), one of the most prevalent internal modifications on mammalian RNAs, regulates RNA transcription, stabilization, and splicing. Growing evidence has focused on the functional role of m 6 A regulators on acute myeloid leukemia (AML). However, the global m 6 A levels after azacytidine (AZA) plus venetoclax (VEN) treatment in AML patients remain unclear. In our present study, bone marrow (BM) sample pairs (including pre-treatment [AML] and post-treatment [complete remission (CR)] samples) were harvested from three AML patients who had achieved CR after AZA plus VEN treatment for Nanopore direct RNA sequencing. Notably, the amount of m 6 A sites and the m 6 A levels in CR BMs was significantly lower than those in the AML BMs. Such a significant reduction in the m 6 A levels was also detected in AZA-treated HL-60 cells. Thirteen genes with decreased m 6 A and expression levels were identified, among which three genes ( HPRT1 , SNRPC , and ANP32B ) were closely related to the prognosis of AML. Finally, we speculated the mechanism via which m 6 A modifications affected the mRNA stability of these three genes. In conclusion, we illustrated for the first time the global landscape of m 6 A levels in AZA plus VEN treated AML (CR) patients and revealed that AZA had a significant demethylation effect at the RNA level in AML patients. In addition, we identified new biomarkers for AZA plus VEN-treated AML via Nanopore sequencing technology in RNA epigenetics.

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