Publication

CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression.

Cell. 2017 Feb 23;168(5):801-816.e13. doi: 10.1016/j.cell.2017.01.021. Epub 2017 Feb 16.

Abstract

DNMT3A mutations occur in ?25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3AR882H, has dominant negative activity that reduces DNA methylation activity by ?80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3AR882 mutations. Non-leukemic hematopoietic cells with DNMT3AR882H displayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing and was essentially absent in AMLs with DNMT3AR882 mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3AR882, while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression.

Authors

Spencer DH, Russler-Germain DA, Ketkar S, Helton NM, Lamprecht TL, Fulton RS, Fronick CC, O'Laughlin M, Heath SE, Shinawi M, Westervelt P, Payton JE, Wartman LD, Welch JS, Wilson RK, Walter MJ, Link DC, DiPersio JF, Ley TJ.