The lifelong natural history of clonal hematopoiesis and its links to myeloid neoplasia.

The study of somatic mutations and the associated clonal mosaicism across the human body has transformed our understanding of aging and its links to cancer. In proliferative human tissues, stem cells compete for dominance, and those with an advantage expand clonally to outgrow their peers. In the hematopoietic system, such expansion is termed clonal hematopoiesis (CH). The forces driving competition, namely heterogeneity of the hematopoietic stem cell (HSC) pool and attrition of their environment, become increasingly prominent with age. As a result, CH becomes progressively more common through life to the point of becoming essentially ubiquitous. We are beginning to unravel the specific intracellular and extracellular factors underpinning clonal behavior, with somatic mutations in specific driver genes, inflammation, telomere maintenance, extraneous exposures, and inherited genetic variation among the important players. The inevitability of CH with age combined with its unequivocal links to myeloid cancers poses a scientific and clinical challenge. Specifically, we need to decipher the factors determining clonal behavior and develop prognostic tools to identify those at high risk of malignant progression, for whom preventive interventions may be warranted. Here, we discuss how recent advances in our understanding of the natural history of CH have provided important insights into these processes and helped define future avenues of investigation.