Support of the Sander Sander Foundation for the investigation of DNMT3A mutations in AML
Up to 25% of all AML tumors
contain DNMT3A mutations by far the most common R882H. In 2018, we identified changes in the
flanking sequence preferences of DNMT3A-R882H (Emperle et al., 2018, Nucl Acids Res). These changes
will be further characterized and investigated with new bioinformatics methods DNA methylation
patterns in human cells and patient data. Moreover, the target genes of the dysregulation by the
R882H mutation will be identified. Tumor cell models for mutant DNMT3A will be developed to study
the effect of DNMT3A mutations on cell proliferation and pathogenic mechanisms and to test DNMT
inhibitors. Further common mutations in DNMT3A will be investigated using similar biochemical,
molecular biological and bioinformatory approaches. Our study is intended to validate the mechanism
of action of the R882H mutation we have found, and to substantially enhance our understanding of
AML tumors with R882H. From the study of the other common mutations in DNMT3A, we expect further
important insights into the fundamental pathogenicity mechanisms of these variants.