CpG Island Hypomethylation May Contribute to AML Initiation

Mutations in the DNA methyltransferase DNMT3A, most commonly DNMT3A^R882H, occur in approximately 25% of patients with acute myeloid leukemia (AML). DNMT3A^R882H 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 DNMT3A^R882 mutations. Whole-genome bisulfite sequencing (WGBS) of hematopoietic cells from a patient with the DNMT3A^R882H allele, but without leukemia, and the patient's wild-type sibling indicated that DNMT3A^R882H is associated with focal methylation loss even in nonleukemic cells. Further, WGBS of primary AML samples revealed that DNMT3A^R882 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 DNMT3A^R882H 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 DNMT3A^R882H-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.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.