Modifiable Drivers of Expansion and Malignant Transformation from Clonal Hematopoiesis

Project Summary/Abstract Clonal hematopoiesis (CH) is an age-associated pre-malignant condition in which the progeny of hematopoietic stem and progenitor cells (HSPCs) with somatic mutations in about 20 genes dominate production of the peripheral blood. While CH can persist without apparent health consequences for decades, it is associated with increased risk for hematologic malignancies as well as all-cause mortality. Extrinsic conditions that favor particular clones may separate asymptomatic CH carriers from those that progress to disease; yet, the specific risk factors that can be modified to influence CH and its sequelae are largely unknown. The overall goal of this Program, with three interactive Projects and two Cores, is to identify modifiable risk factors of CH-associated HSPC expansion and subsequent malignant transformation, with a long-term view toward developing cancer prevention strategies. A major feature of our Program is the use of novel mouse models to mimic CH and test mechanisms that drive clone expansion and malignancy. In addition, our Program harnesses data from the exceptional Atherosclerosis Risk in Communities (ARIC) study – which has followed more than 9,500 diverse participants (27% Black, 55% female) over 30 years – to evaluate CH and malignancy risk in older adults. Project 1 models CH in mice, with an emphasis on HSPCs bearing mutations in epigenetic regulators (particularly Dnmt3a and Tet2), to determine how inflammatory stress and metabolic changes promote expansion, including cooperation between clones, and malignant transformation. Project 2 focuses on CH with DNA Damage Response (DDR)-associated gene mutations, and how exposure to genotoxic stress from chemotherapy and smoking enables clonal dominance and malignant transformation in mice. Both Projects 1 and 2 explore potential interventions to suppress clone expansion. Project 3 analyzes the contribution of inflammation and DNA damaging exposures to clonal expansion and malignant transformation in the ARIC cohort, capitalizing on clinical, proteomic, methylation, whole exome sequencing, and metabolomic data already available. Project 3 will also perform single cell sequencing to determine changes in CH clonal contribution over time, including clonal interactions, and the evolution to malignancy in the context of external stressors. The Projects are highly interactive, with Projects 1 and 2 iteratively testing the causal and mechanistic influence of risk factors nominated by preliminary studies and by Project 3, and Project 3 performing additional analyses to validate findings generated by Projects 1 and 2. Projects 1 and 2 are mutually enhanced by shared approaches and data. Together, all Projects will deconvolute the role of risk factors to CH and malignancy. The Program is supported by a Single Cell Sequencing and Bioinformatics Core and an Administrative Core. By focusing on modifiable risk factors, we can stratify the risk of hematologic malignancy to inform clinical guidance of individuals with CH. Our expert team combines clinicians and scientists with long track records of successful collaboration. Together we will address this critical problem for human health and longevity.