Generating mouse models of clonal hematopoiesis to study the potential of apsirin to prevent cancers

Clonal haematopoiesis of indeterminate potential (CHIP), defined as the presence of blood cancer-associated mutations with a variant allele frequency (VAF) > 2% but normal blood counts, is a disease of ageing affecting >1 million Australians over 70 years. CHIP rarely progresses to blood cancer but is associated with increased all-cause mortality attributed mainly to increased cardiovascular disease related to a pro-inflammatory state. However, disease associations with CHIP have been made from observational studies that have inherent selection biases and confounding risk factors. Large, longitudinal studies that measure CHIP, inflammatory cytokines and clinical outcomes are needed to understand its clinical implications and identify potential interventions. Leveraging the ASPirin in Reducing Events in the Elderly (ASPREE) study, we have established the world’s largest, longitudinal cohort study of CHIP. ASPREE-CHIP is internationally unique, with serial blood and urine samples linked to high quality longitudinal clinical data in a randomised trial of aspirin for primary prevention in healthy 70y+. We have developed an amplicon-based assay to measure CHIP in 10,073 participants. Overall, 34% had CHIP, but only the 6% of participants with a large CHIP clone (VAF >10%) had 57% increased all-cause mortality that was surprisingly driven by increased cancer-related but not cardiovascular mortality. Most remarkably, aspirin almost completely abrogated the increased risk of cancer in those with large CHIP. This project will establish mouse models of CHIP using transplant of mutant stem cells from DNMT3A or TET2 mutant mice to test hypotheses arising from the ASPREE-CHIP study. Specifically, you will use FACS-isolation of hematopoietic subsets (stem cells, macrophages, T-cells) to measure production of pro-inflammatory cytokines (Aim 1), treat mice with pro-inflammatory cytokines (IL-1 beta, IL-6, TNF alpha) to determine if CHIP-mutant cells have a selective advantage in the setting of a pro-inflammatory environment (Aim 2), use monoclonal antibodies against pro-inflammatory cytokines to identify targets for suppressing CHIP (Aim 3) and establish heart disease and cancer models (breast, prostate) in CHIP mice to understand why aspirin reduces cancer but not heart disease in CHIP. This project is ideally suited for an MD/PhD but Aim 1 could form the basis of an honours project with the goal of extending to a PhD. During your studies, you will become an expert in experimental mouse models, flow cytometry, ELISA and RNA-seq. Results from your studies will provide the platform for developing Phase II trials of therapeutics for slowing the growth of CHIP. In addition, this project could have profound impact in the field of primary prevention of cancer, where CHIP could be used as a biomarker in healthy elderly for the use of aspirin, which could prevent 3,000 cancers per year in Australia alone.