Integrated single cell multi-omic characterization and clonal tracing in clonal hematopoiesis

• Applicants: Professor Dr. Frederik Damm; Dr. Leif Ludwig
• Subject Area: Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497580500

Clonal hematopoiesis of indeterminate potential (CHIP) specifies an ageing-related state characterized by the acquisition of somatic mutations in hematopoietic stem cells (HSCs) and is associated with an increased risk of cardiovascular diseases (CVD), hematologic malignancies (HM) and all-cause mortality. CHIP-associated mutations affect malignancy-associated genes, that broadly fall into three major categories of genes including epigenetic regulators (e.g. DNMT3A, TET2, ASXL1), spliceosome (e.g. SF3B1) and DNA damage genes (e.g. PPM1D, TP53). These mutations provide hematopoietic stem cells with a competitive advantage, including an increased proliferative drive, self-renewal potential and/or capacity to evade death from cellular damage. Over time, these mutated HSCs thereby form a genetically distinct and expanded pool of differentiated blood cells that carry the same somatic variant. The prevalence of clonal hematopoiesis increases with age, and it affects more than 20-30% of the elderly population. A growing body of evidence suggests a self-perpetuating circle of inflammation and clonal expansion as cause and result of CHIP. However, the various factors underlying heterogeneity of CHIP-associated diseases remain poorly defined, also considering the observation that the vast majority of affected individuals do not develop CVD or HM and remain ostensibly healthy for many years. Overall, the lack of recognizable factors that predict the precise risk of a benign or more pathological outcome and potential ability to intervene therapeutically presents a challenge for the clinical community.In light of these challenges, we aim to assess the contribution of the different layers, specifically genetic and non-genetic factors that contribute to the development of CH associated phenotypes. To achieve this, we will perform comprehensive single cell multi-omic characterizations in conjunction with mutation-based clonal readouts to decipher cellular states and predictive biomarkers that associate with distinct disease phenotypes at the cellular and genomic level in a cohort of CH. We aim to address the following specific questions: (i) how does a given somatic CH mutation influence transcriptomic programs in relation to cell identity? (ii) Do individuals with CH show altered accessible chromatin states and heterogeneity of peripheral blood myeloid cells? (iii) Can different genomic states be characterized in the stem cell compartment of individuals with CH and do they differ with respect to various CH-associated diseases?

• DFG Programme: Research Grants