Project Details
Projekt
Targeting aberrant chromatin states during clonal evolution and diversification in MPN
Applicants
Professor Dr. Frederik Damm; Dr. Florian Perner
Subject Area
Hematology, Oncology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517204983
Clonal evolution and diversification is an important contributor to therapy-resistance and dis-ease progression in MPN patients. A growing body of evidence indicates that both genetic and non-genetic factors such as aberrant chromatin states significantly contribute to intra-tumoral heterogeneity (ITH). While the importance of genetic and non-genetic ITH for disease pathogen-esis and treatment response has been largely investigated in solid cancers, only few studies ad-dressed this important topic in MPN patients. In this project, we will comprehensively charac-terize ITH and investigate how aberrant epigenetic regulation contributes to clonal diversifica-tion and disease progression in MPN. We hypothesize that specific chromatin modifiers, includ-ing the Menin-MLL1 complex as well as the histone demethylase LSD1, are critical for the estab-lishment of pathogenic gene expression programs in clonal subpopulations of blood cells. Based on published and our preliminary data, we speculate that treatment with potent and selective inhibitors of these chromatin binding proteins can reverse the aberrant chromatin state and gene expression signatures in a genotype selective manner and target pathogenic clones in xen-ograft models of MPN. To this aim we will address three main research topics: i) reconstruction of lineage architecture and clonal heterogeneity in high-risk MPN, ii) definition of lineage-specific transcriptional signatures and chromatin accessibility patterns during disease progres-sion in MPN, and iii) to assess the therapeutic efficacy of chromatin modifying therapies in xeno-graft models of high-risk MPN. A variety of highly innovative and modern technologies such as single-cell DNA genotyping, whole-genome and ATAC-sequencing will be coupled with respec-tive in vitro and in vivo models in a combined forward/reverse translational manner. The project will largely benefit from our close interactions within the entire consortium, as well as the German Study Group (GSG) MPN-BioRegistry biobank. Data will be shared within the consortium and will foster synergy among the projects.
DFG Programme
Research Units
