Dynamics of clonal hematopoiesis and risk of hematologic malignancy

The age-related expansion of hematopoietic stem cell clones carrying somatic mutations is known as clonal hematopoiesis and is linked to hematologic malignancies, cardiovascular diseases, and increased mortality. As the risk for adverse outcomes increases substantially with clone size, a precise understanding of the mechanisms that promote clonal expansion is crucial to identify potential therapeutic targets. Clonal expansion and progression to myeloid malignancies are driven by a complex interplay of cell-intrinsic and extrinsic factors that remain incompletely understood. Here, we review how recently proposed methods to estimate clonal expansion rates have been implemented to study the natural history of clonal hematopoiesis and identify factors that promote clonal expansion. We discuss how these factors relate to progression to myeloid malignancies and recapitulate recent risk prediction models. While we are still in the early stages of understanding clonal expansion, analysis of large-scale biobank data in combination with experimental models will help to discover causal factors promoting or suppressing clone growth, define mechanisms, and identify potential targets for clinical intervention in the future.