Elucidating the Mechanisms of Clonal Expansion in Clonal Hematopoiesis - A Large-Scale Population-Based Study

• Applicant: Dr. Christopher Maximilian Arends
• Subject Area: Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 532474220

As we age, changes occur in the DNA of blood stem cells due to frequent cell division or external influences. This can result in the dominance of a so-called clone (i.e. the set of blood cells derived from one stem cell) that contributes disproportionately to blood formation. This phenomenon is called clonal hematopoiesis of indeterminate potential (CHIP) and can be detected in 10-20% of individuals over 60 years of age. CHIP is of increasing medical interest, as affected individuals have a severely increased risk of blood cancer and cardiovascular diseases. All previous studies suggest that these risks are greater the higher the percentage of altered blood cells. Therefore, a better understanding of the mechanisms that lead to the expansion of altered blood cells can significantly improve the early detection and prevention of these diseases. In the proposed project, genetic data from the blood of approximately 500,000 participants in the UK Biobank study will be analyzed. Using a recently developed tool, the growth rate of CHIP clones can be reconstructed from this data. We will perform a genome-wide association study to identify inherited factors of clonal expansion. Additional data systematically documented within the UK Biobank study, such as concentrations of certain metabolites in the blood, can be used to determine extrinsic factors that influence clonal expansion. Subsequently, the precise molecular mechanisms of these factors will be investigated in cell culture models of genetically modified blood stem cells. The results of this work will contribute to a better understanding of the development of blood cancer and cardiovascular diseases and help to identify therapeutic targets to inhibit the growth of clones and attenuate the associated negative health consequences.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Siddhartha Jaiswal