We profiled genome-wide DNA methylation patterns in <i>DNMT3A</i> c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo <i>DNMT3A</i> variants.
R882H specific DNA hypermethylation events in AML patients were accompanied by R882H specific mis-regulation of several genes with strong cancer connection, which are potential downstream targets of R882H.
DNMT3A R882H occurs frequently in various cancers, including acute myeloid leukemia, and our results suggest that the effects of R882H and other <i>DNMT3A</i> mutations may go beyond changes in DNMT3A methylation activity.
The importance of the tetramer structure and cooperative mechanism is emphasized by the observation that the R882H mutation in the dimer interface of DNMT3A is highly prevalent in acute myeloid leukemia and leads to a substantial loss of its activity.
This report represents the first documentation of the same variant (DNMT3A p.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML.
Our results provided novel insight into the role of the DNMT3A R882H mutation in AML pathogenesis and suggested that targeting the cellular GSH synthetic pathway could enhance the current therapy for AML patients with the DNMT3A R882H mutation.
To explore the features of human AML with the hotspot <i>DNMT3A</i> R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin<sup>-</sup>Sca1<sup>+</sup>cKit<sup>+</sup> cell compartments.