RT Journal Article SR Electronic T1 Genome-wide analysis of focal DNA hypermethylation in IDH-mutant AML samples JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.03.03.433799 DO 10.1101/2021.03.03.433799 A1 Elisabeth R. Wilson A1 Nichole M. Helton A1 Sharon E. Heath A1 Robert S. Fulton A1 Jacqueline E. Payton A1 John S. Welch A1 Matthew J. Walter A1 Peter Westervelt A1 John F. DiPersio A1 Daniel C. Link A1 Christopher A. Miller A1 Timothy J. Ley A1 David H. Spencer YR 2021 UL http://biorxiv.org/content/early/2021/05/26/2021.03.03.433799.abstract AB Recurrent mutations in IDH1 or IDH2 in acute myeloid leukemia (AML) are associated with increased DNA methylation, but the genome-wide patterns of this hypermethylation phenotype have not been comprehensively studied in AML samples. We analyzed whole-genome bisulfite sequencing data from 15 primary AML samples with IDH1 or IDH2 mutations, which identified ~4,000 focal regions that were uniquely hypermethylated vs. normal CD34+ cells. These regions had modest, but significant, hypermethylation in AMLs with biallelic TET2 mutations, and 5-hydroxymethylation levels that were dependent on functional TET2, indicating that hypermethylation in these regions is caused by inhibition of TET-mediated demethylation. Focal hypermethylation in IDHmut AMLs occurred in regions with low methylation in normal CD34+ cells, implying that DNA methylation and demethylation are active at these loci. AML samples containing IDH and DNMT3AR882 mutations were significantly less hypermethylated, suggesting that methylation in these regions is mediated by DNMT3A. IDHmut-specific hypermethylation was highly enriched for enhancers that form direct interactions with genes involved in normal hematopoiesis and AML, including MYC and ETV6. These results suggest that focal hypermethylation in IDH-mutant AML occurs by altering the balance between DNA methylation and demethylation, and that disruption of these pathways at enhancers may contribute to AML pathogenesis.Competing Interest StatementThe authors have declared no competing interest.