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

DNMT3A mutations occur in similar to 25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3A R882H, has dominant negative activity that reduces DNA methylation activity by similar to 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 DNMT3A(R882) mutations. Nonleukemic hematopoietic cells with DNMT3A(R882H) 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 DNMT3A(R882) 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 DNMT3A(R882), while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression.