FOR 5643:  Clonal hematopoiesis: Pathomechanisms and clinical consequences in the heart and blood

• Subject Area: Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515629962

The acquisition of somatic mutations in hematopoietic stem/progenitor cells in myeloid-leukemia-related genes coincides with the normal aging process and leads to the outgrowth of mutated blood cell clones (clonal hematopoiesis, CH). CH is highly prevalent in individuals over the age of 60. Intensive research by us and others over the last 5 years have revealed that CH has major pathophysiological implications. While CH is associated with enhanced risk to progress into hematologic malignancies, CH has emerged as an unexpected, independent risk factor and driver of atherosclerosis, coronary heart disease, heart failure and aortic valve stenosis. The topic of utmost medical interest requires a transdisciplinary Research Unit (entitled HERZBLUT) crossing the boarders of hematology and cardiovascular medicine. We present a strong team of world-leading experts in these fields and emerging junior investigators to pair strong life science and medical research experience with sophisticated technologies and advanced research approaches. Basic and clinician scientists closely interact to transfer the knowledge from molecular and cell-based models to preclinical models and clinical application, and to enable the reverse translation of primary material from well characterized patient cohorts back to the lab. The restriction on certain genes (DNMT3A, TET2, PPM1D, SRSF2, SF3B1), mutations and CH-associated diseases (heart failure, valve stenosis, pulmonary hypertension, acute myeloid leukemia) will generate high synergisms in sharing common technologies, models, and research tools within HERZBLUT, and help to build a broad and unifying picture of overarching disease mechanisms. We propose here a comprehensive and highly synergistic work program to follow two major aims: a) to target the pathomechanisms of CH for therapeutic applications and b) to interrogate CH development and progression in the context of CH-associated diseases. With HERZBLUT, we pursue following objectives: (1) To promote precision biology in the field of CH and its associated diseases of the heart and the blood by studying the molecular and cellular pathomechanisms. (2) To exploit mechanistic findings for novel individualized therapies, promoting precision medicine. (3) To promote junior scientists and clinicians for basic and translational research. (4) To recruit and promote outstanding female scientists and clinicians. (5) To facilitate the development of diagnostic and therapeutic approaches by patenting and exploiting our newly gained knowledge. (6) To install a broad array of measures addressing public outreach for the scientific and medical community and for the general public. The exquisite composition of HERZBLUT, paired with an excellent and stringent research plan, will ensure our efforts in developing critical knowledge and in translating tools for clinical management of CH and CH-associated diseases in the heart and blood.

• DFG Programme: Research Units

Projects

• Acceleration of clonal hematopoiesis mediated by the bone marrow niche in heart failure (Project B3) (Applicants Cremer, Sebastian ;  Kokkaliaris, Ph.D., Konstantinos )
• Comparative functional characterization of distinct CH mutations recurrent in cardiovascular disease and myeloid malignancies (Project B1) (Applicants Schnütgen, Frank ;  Serve, Hubert )
• Coordination Funds (Applicant Rieger, Michael )
• Epigenetic-metabolic contribution to inflammatory phenotypes of CH in pulmonary hypertension (Project A3) (Applicant Savai Pullamsetti, Soni )
• Identification and targeting of mutated PPM1D for preventing cardiovascular events and therapy-related myeloid neoplasms in cancer survivors (project A5) (Applicant Cremer, Anjali )
• In vitro CHIP modelling for therapeutics discovery and mechanistic dissection (project A4) (Applicant Krishnan, Ph.D., Jaya )
• Interaction of clonal hematopoiesis-driver mutations with heart failure (Project A1) (Applicants Dimmeler, Stefanie ;  Zeiher, Andreas Michael )
• Mechanisms of aortic valve calcification driven by clonal hematopoiesis mutations (Project A2) (Applicants Abplanalp, Ph.D., Wesley ;  Mas-Peiro, Silvia )
• Quantitative assessment of clonal architecture, stem cell competition and lineage fate in CH (Project B2) (Applicant Rieger, Michael )
• Rewiring leukemogenic transformation of GATA1s-mediated CH by KANSL1 loss-of-function mutations (Project B4) (Applicants Klusmann, Jan-Henning Cornelius ;  Vermunt, Ph.D., Marit )

• Spokesperson: Professor Dr. Michael Rieger