Illustration of the substrate specifcity of DNMT3A R882H

New publication in "Nucl. Acids Res."

October 20, 2019 /

Pathogenic mechanism of the DNMT3A R882H mutant

New publication in "Nucl. Acids Res."

The heterozygous R882H mutation in the DNMT3A DNA methyltransferase occurs frequently in Acute myeloid leukemia (AML) patients and it has an early role in tumorigenesis. The R882H mutation is located at DNA binding site of DNMT3A, but its pathogenic mechanism is not completely understood. Previously, we showed that this mutation leads to massive changes in the flanking sequence preferences of DNMT3A, which provided a novel mechanistic approach to the understanding of the pathogenic effects of this mutation (Emperle, et al. 2018, Nucleic Acids Res. 46(6):3130-3139). In the current work we applied a newly developed Next Generation Sequencing-coupled methylation assay that allowed us to define the altered flanking sequence preferences in great details and enabled comparison with genomic methylation pattern in human cells. Using this method, we detected characteristic changes in the DNA methylation patterns in human cells after expressing R882H and in AML patients with R882H mutations when compared with patients not carrying R882H. Based on these data, we identify a list of R882H specifically hypermethylated and differentially expressed genes with known connection to cancer and AML.


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