DNMT3A and acute myeloid leukemia: This study, through structural and biochemical characterizations of DNMT3AR882H–DNA interaction, reveals multiple functional impacts of the AML-associated hotspot mutation DNMT3A R882H: The R882H mutation not only reduced the protein–DNA interactions at the RD interface, but also impairs the TRD loop-mediated CpG recognition, which may together contribute to aberrant CpG methylation in AML.