Dynamic alterations of the transcriptome-wide m6A methylome in cytogenetically normal acute myeloid leukaemia during initial diagnosis and relapse.

Accumulating studies have indicated that N6-methyladenosine (m6A) plays an important role in acute myeloid leukaemia (AML). However, little is known about the m6A methylome at a transcriptome-wide scale in AML patients. We obtained three pairs of bone marrow (BM) samples from cytogenetically normal AML patients at the timepoints of diagnosis (AML) and relapse (R_AML) and three BM samples from healthy donors used as normal controls (NCs). Methylated RNA immunoprecipitation next-generation sequencing (MeRIP-Seq) was conducted to identify differences in the m6A methylomes between AML and NC and between R_AML and AML. We identified a total of 11,076 and 11,962 differential m6A peaks in AML and R_AML group, respectively. These dysregulated m6A peaks were detected on all chromosomes, especially chr1, chr19 and chr17, and were mainly enriched in 3′ untranslated regions, stop codon and coding sequence regions. Moreover, GO and KEGG analyses indicated that m6A -modified genes were significantly enriched in cancer-related biological functions and pathways. Additionally, we identified a link between the m6A methylome and RNA transcriptome via combined analyses of MeRIP-seq and RNA-seq data. In addition, 5 genes, HSPG2, HOMER3, TSPO2, CXCL12 and FUT1 regulated by m6A modification potentially, were shown to be related to the prognosis of AML patients. Additionally, we detected the mRNA expression of major m6A regulators and potential target mRNA on the leukemogenesis and found that the expression of IGF2BP2, HSPG2 and HOMER3 were upregulated in AML at the time of diagnosis. Moreover, their expression became downregulated after remission and then elevated again at relapse. Our study provides the first data on the differential m6A methylome in AML patients during initial diagnosis and relapse. This study demonstrates a novel relationship between m6A modification and AML relapse and paves the way for further studies aimed at elucidating the epigenic mechanisms involved in the relapse of AML. • M6A methylation is widespread during both the onset and relapse of AML. • Differentially methylated genes are involved in important biological processes and signalling pathways in both de novo AML and relapsed AML. • Genes regulated by m6A modification are associated with the overall survival of AML patients. [ABSTRACT FROM AUTHOR]