Multiomics analysis focusing on genome-wide DNA methylation in paediatric acute promyelocytic leukaemia

We conducted a multiomics analysis of paediatric acute promyelocytic leukaemia (APL) in 36 patients enrolled in the Japanese AML-P05 study. Targeted deep sequencing identified EP300 mutations (n = 2) and MYC-internal tandem duplication (ITD) (n = 1), which have not been previously reported in APLs. DNA methylation analysis classified 34 paediatric APLs into two groups: hypermethylation and hypomethylation. Patients in the hypermethylation group had significantly worse outcomes compared to those in the hypomethylation group (3-year overall survival: 80% vs. 100%, p = 0.043; 3-year event-free survival: 73% vs. 95%, p = 0.049). Remarkably, the EBF1-binding motif was enriched in 82.3% of the CpG sites that were differentially methylated between the hyper- and hypomethylation groups, and these sites were predominantly located in enhancer regions. Among the 1427 genes that were significantly differentially expressed between the two groups, EP300 was significantly downregulated in the hypermethylation group. Pathway analyses revealed global transcriptional downregulation in the hypermethylation group; however, MYC, a known EP300-repressed gene, was upregulated within the G2M checkpoint. Our findings suggest a potential link among enhancer-based epigenetic dysregulation involving DNA methylation at EBF1-binding sites, EP300 dysfunction and MYC activation. These alterations may contribute to disease heterogeneity and prognosis in paediatric APL.