Epigenetic identity in AML is mostly dependent on disruption of non-promoter regulatory elements and reveals potentially antagonistic effects of mutations in epigenetic modifiers [mouse]

Aberrant DNA methylation of gene promoters is a hallmark of AML. To define more precisely how cytosine methylation is redistributed in AML, we performed base-pair resolution methylome sequencing in 119 patients. We find that leukemic DNA methylation patterning is tightly linked to somatic mutations and primarily driven by regulatory elements outside of promoters and by CpG shores as opposed to CpG islands. Active enhancers displayed much stronger focal differential methylation than promoters and were generally aberrantly hypomethylated except in IDH2 mutant and CEBPA silenced AMLs. AMLs with dominant hypermethylation feature greater epigenetic disruption of promoters. Those with dominant hypomethylation, such as DNMT3A mutated AMLs, display greater disruption of distal and intronic regions. IDH mutant AMLs manifest profound hypermethylation whereas DNMT3A mutant AMLs manifest profound hypomethylation of a different set of CpGs. In striking contrast, AMLs with co-occurring IDH1 and DNMT3A mutations exhibited epigenetic antagonism in which most CpGs affected by either mutation alone were no longer affected in the double mutant cases. Overall design: Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) was performed on Idh2, Dnmt3a, and Idh2/Dnmt3a mutant mice. Idh2 mouse profiling is detailed in PMID: 28193779 and deposited here (LSK controls are deposited under GSE57114). Dnmt3a mutant and LSK control mouse profiling is detailed in PMID: 26710888 and deposited under GSE86827 with a set of LSK controls under GEO series GSE74165