Signaling properties of driver mutations in clonal hematopoiesis of indeterminate potential (CHIP) as targets for diagnostics and therapeutic intervention

• Applicant: Professor Dr. Carsten Müller-Tidow
• Subject Area: Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508481183

Somatic mutations in hematopoietic stem cells which induce clonal expansion are commonly acquired during human aging. Clonal hematopoiesis of indeterminate potential (CHIP) constitutes an important risk factor for the development of hematological malignancies and cardiovascular disease and is associated with an increased all-cause mortality. A growing body of evidence suggest that dysregulated inflammation contributes to clonal expansion and associated comorbidities such as inflammation from previous infections, pre-existing comorbidities or low-grade inflammation occurring with aging (inflammaging). CHIP-specific molecular features might be important targets for diagnostics and development of specific therapies. In this project we aim to identify CHIP associated signaling pathways and surface marker expression patterns with advanced multi-omics single cell analysis tools. In preliminary work for this proposal we analyzed CHIP mutations in mobilized stem cell products from more than 600 patients undergoing stem cell leukapheresis. Also, we established a specific bioinformatics tool set for the analyses in this project. Multi-omics single cell analyses will be used to identify deregulated signaling pathways and surface marker patterns (CITE-Seq) across diverse CHIP mutations and cell types. Subsequently, we will overexpress and knockout CHIP-associated expression patterns/signaling pathways in CD34+ hematopoeitic stem cells (HSC) from cord blood and analyse in vitro and in vivo whether modification of signaling/inflammatory genes phenocopies candidate driver mutations. For the top-regulatory pathways/ targets for which specific inhibitors are available we will analyze in vitro- drug responses and will perform in vivo xenograft transplantation studies to evaluate the potential of the respective drugs to preferentially eradicate CHIP clones. Taken together, this project will reveal pathways/regulatory genes which might be used for diagnostics and potentially for therapeutic applications to suppress CHIP clones.

• DFG Programme: Research Grants