Targeting aberrant DNA methylation in myeloproliferative neoplasms

• Applicants: Helene Gleitz, Ph.D.; Professor Dr. Wolfgang Wagner
• Subject Area: Hematology, Oncology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417911533

Epigenetic modifications seem to play a central role for development of myeloproliferative neoplasms (MPN) and genes involved in the regulation of DNA methylation, such as DNMT3A and TET2, are frequently mutated. Various studies have also demonstrated aberrant DNA methylation in MPN patients as compared to healthy controls. So far, a systematic evaluation of characteristic DNA methylation patterns of the MPN clone, which might support risk stratification and therapeutic decision-making, remains elusive. It is unclear whether aberrant DNA methylation is directly evoked by JAK2V617F mutations, and if it is co-regulated on different alleles and at different sites in the genome. Interactions of the MPN clone and its progeny with the bone marrow stromal niche have been shown to drive myelofibrosis. It is therefore likely that epigenetic aberrations are also present in the stromal compartment and contribute to disease onset. Lastly, it remains unknown whether aberrant DNA methylation changes are functionally relevant to MPN development and if they can be targeted to interfere with the aberrant epigenetic network and disease progression. In this project we will (1) identify characteristic DNA methylation patterns in the malignant MPN clone and dissect networks of CG dinucleotides that are coherently modified to find epigenetic hubs that might entail epigenetic aberrations at other sites in the genome. (2) Concurrently, we will investigate epigenetic changes in the bone marrow stromal compartment during development of primary myelofibrosis. The dynamics of enhancer activation will be investigated with the newly-developed “Dcm-time machine” (Dcm-TM) methylation technology. (3) To investigate novel therapeutic approaches for early intervention in MPN, we will modulate DNA methylation at epigenetic hubs using CRISPR-guided modifications or hypomethylating agents in iPSC-derived hematopoietic cells carrying JAK2V617F mutations and murine models of myelofibrosis. In summary, we expect to find aberrant DNA methylation networks that are co-regulated in the malignant clone, together with dynamic epigenetic modifications in the stromal compartment, which could be targeted to identify novel targets for early therapeutic intervention.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 344: Untangling and Targeting Mechanisms of Myelofibrosis in Myeloproliferative Neoplasms (MPN)
• International Connection: Netherlands