FOR 5659:  TARGET-MPN: TARgetinG disease pErsisTence and progression of MyeloProliferative Neoplasms (MPN)

• Subject Area: Medicine
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517204983

Myeloproliferative neoplasms (MPN) are rare malignant disorders of the hematopoietic stem cell, which mainly affect older individuals at an annual incidence of 1.5-2.5 / 100,000. Although symptomatic treatment approaches have been developed, allogeneic stem cell transplantation is so far the only therapy that can eradicate the malignant MPN stem cells. However, significant morbidity and mortality limit this option so that it remains reserved for a subgroup of fit, high-risk patients in advanced disease stages. Beyond this aggressive treatment option, there is no available therapy that modifies these diseases or prevents disease progression. Although disease dynamics and the mutational landscape of MPN have been defined in very detail, several critical aspects of disease persistence and progression remain elusive: (1) although the mutational landscape appears similar among MPN subtypes, how do functional dependencies and vulnerabilities differ, (2) how are these aberrations modulated to generate different disease phenotypes, (3) which factors influence or generate functional dependencies and (4) what defines and predicts disease progression beyond the presence of specific genetic mutations, especially in regard to transcriptional and epigenetic regulation, cell signaling and cell-cell interaction. The proposed consortium will therefore focus on mechanisms and molecules that are essential for disease persistence and progression irrespective of the clinical phenotype. The overriding aim of this research group is to identify and functionally characterize molecular targets in order to develop personalized therapies to prevent disease progression and eventually eradicate the persistent MPN cells. Using multi-omics and single cell technologies (genomic, epigenomic, transcriptomic and proteomic profiling) in primary murine and human MPN samples, CRISPR-Cas9-based functional studies, immune profiling and mouse models (genetically engineered strains and patient-derived xenografts), this group of researchers will clarify basic mechanisms of disease persistence and progression and define functional dependencies for translational therapeutic use. Researchers in this consortium have already collaborated on various aspects of MPN biology. This application will create additional synergy through a consortium that may serve as a blueprint for phenotype-agnostic approaches in other hematopoietic cancers.

• DFG Programme: Research Units
• International Connection: Austria

Projects

• A bad seed in bad soil: understanding the effect of altered NFE2 levels on HSC cell fate, MPN-progression and its modification by the bone marrow niche (Applicant Pahl, Heike L. )
• Characterizing the impact of inflammatory signaling on MPN disease persistence (Applicant Jost, Philipp )
• Coordination Funds (Applicant Heidel, Florian )
• Identification of functional dependencies to prevent MPN disease progression (Applicant Heidel, Florian )
• Identification of niche factors and inflammatory cytokines driving clonal progression in MPN (Applicant Dierks, Christine )
• Interoperable standardized and harmonized TARGET-MPN data platform (Applicants Bullinger, Lars ;  Thun, Sylvia )
• Longitudinal comprehensive transcriptome analyses to unravel disease persistence and evolution in MPN (Applicants Bullinger, Lars ;  Döhner, Konstanze )
• Targeting aberrant cell signaling to eradicate persistent MPN cells (Applicant Jayavelu, Ph.D., Ashok Kumar )
• Targeting aberrant chromatin states during clonal evolution and diversification in MPN (Applicants Damm, Frederik ;  Perner, Florian )
• Targeting immune escape mechanisms to eliminate persisting MPN cells (Applicant Zeiser, Robert )
• Targeting Kindlin-3-mediated integrin activation and signaling to eradicate persistent MPN clones (Applicant Koschmieder, Steffen )

• Spokesperson: Professor Dr. Florian Heidel