Targeting of DNA Methylation Networks in Acute Myeloid Leukemia

• Applicants: Professor Dr. Thomas Stiehl; Professor Dr. Wolfgang Wagner
• Subject Area: Hematology, Oncology ; General Genetics and Functional Genome Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561150360

Acute myeloid leukemia (AML) is associated with a fundamental reconfiguration of the DNA methylation pattern in the malignant clone. So far, the mechanisms governing these changes and their functional relevance remain unknown. In our previous work, we demonstrated that there exist genome-wide modifications of DNA methylation, which are highly reproducible across the AML subtypes. Furthermore, we showed that the aberrant DNA methylation patterns are assimilated on homologous chromosomes. In this project, we aim to elucidate the network of AML-related DNA methylation changes and its potential regulators. We will delineate AML-associated epigenetic modifications through a comprehensive analysis of DNA methylation profiles, also with regard to cell-type associated characteristics, different driver mutations and other myeloid malignancies. We will also investigate potential bystander modifications in the non-malignant cells that may persist in patients without measurable residual disease after treatment. Initial network analysis of AML-associated DNA methylation changes indicated hubs of co-regulated epigenetic modifications. We will explore potential mechanisms leading to the formation of these hubs and develop a computational framework to analyze the molecular sequel of epigenetic aberrations during disease development, similar to genetic aberrations. Furthermore, we will explore dynamics of AML-associated DNA methylation in colony forming units. Finally, we propose utilizing CRISPR technology for targeted modulation of identified epigenetic networks in vitro. We anticipate that epigenetic editing at AML-associated regions will also interfere with genome wide DNA methylation patterns related to AML. The functional sequel of these epigenetic modifications will be tested in AML cell lines and primary cells. Our interdisciplinary project could significantly enhance understanding of AML biology. Through the combination of experiments and computational tools, we aim not only to validate the functional relevance of epigenetic networks but also to pave the way for novel therapeutic strategies aimed at rectifying aberrant DNA methylation patterns in AML.

• DFG Programme: Research Grants