DNMT3AR882 mutations induce focal hypomethylation in AML cells and normal hematopoietic cells.
Major finding: DNMT3AR882 mutations induce focal hypomethylation in AML cells and normal hematopoietic cells.
Concept: CpG island hypermethylation is a consequence of rapid cell growth and is independent of gene silencing.
Impact: CpG island hypermethylation may be not a pathogenic change, but a consequence of proliferative stress.
Mutations in the DNA methyltransferase DNMT3A, most commonly DNMT3AR882H, occur in approximately 25% of patients with acute myeloid leukemia (AML). DNMT3AR882H mutations occur early in the development of leukemia and act in a dominant negative manner to reduce DNA methylation activity. However, it is not clear how DNMT3A-mediated methylation changes contribute to leukemogenesis, prompting Spencer and colleagues to investigate genome-wide DNA methylation patterns in primary AML samples and cell lines with and without DNMT3AR882 mutations. Whole-genome bisulfite sequencing (WGBS) of hematopoietic cells from a patient with the DNMT3AR882H allele, but without leukemia, and the patient's wild-type sibling indicated that DNMT3AR882H is associated with focal methylation loss even in nonleukemic cells. Further, WGBS of primary AML samples revealed that DNMT3AR882 mutations were associated with enhanced focal hypomethylation in CpG dense regions, whereas DNMT3A-wild-type AML was associated with enhanced CpG island hypermethylation. These hypomethylated and hypermethylated regions were associated with distinct genomic and epigenomic features; however, mutant DNMT3A did not substantially alter the epigenetic marks or transcriptional activity of nearby genes. Although DNMT3A–wild-type AML was associated with hypermethylated CpG islands, the hypermethylation was not linked to gene silencing, suggesting that AML-associated gene silencing was more dependent on AML “state” than on hypermethylation of CpG island promoters. Moreover, DNMT3A-mediated hypermethylation of CpG islands occurred in nontransformed primary hematopoietic stem/progenitor cells during cytokine-induced proliferation, and DNMT3AR882H AML cells had largely overlapping regions of hypomethylation that developed before the onset of leukemia, indicating that CpG island hypomethylation may be an AML-initiating phenotype in DNMT3A-mutant cells. Collectively, these findings suggest that DNMT3AR882H-induced CpG island hypomethylation may contribute to the initiation of AML and that CpG island hypermethylation may be a consequence of cellular proliferation and not a pathogenic driver.
Spencer DH, Russler-Germain DA, Ketkar S, Helton NM, Lamprecht TL, Fulton RS, et al. CpG island hypermethylation mediated by DNMT3A Is a consequence of AML progression. Cell 2017;168:801–16.
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