Clonal haematopoiesis to clonal cytopenias: unravelling disease evolution over time

Clonal haematopoiesis refers to the presence of somatic mutations in haematopoietic stem and progenitor cells, accompanied by the expansion of high-fitness clones over time. Age-related clonal haematopoiesis arises from ageing-related DNA damage and is associated with haematological neoplasms and coronary artery disease. Genotoxic therapies can promote the selection of somatic mutations, leading to therapy-related clonal haematopoiesis. Clonal haematopoiesis in acquired or inherited bone marrow failure syndromes and germline predispositions leads to clonal expansion, where fitness constraints on haematopoietic stem cells drive mutation acquisition. When clonal haematopoiesis occurs in the context of persistent unexplained cytopenias, with somatic mutations driving haematopoietic dysfunction, it is referred to as clonal cytopenias of undetermined significance (CCUS). CCUS is a precursor to myeloid neoplasms, with variable progression rates. In this Review, we summarise the current state of knowledge, offering critical insights into the molecular evolution of, and diagnostics and risk assessment for clonal haematopoiesis and CCUS. We highlight the interplay between ageing and environmental factors in the progression to haematological neoplasms and discuss challenges for risk stratification and disease monitoring.