Clonality in Preleukemic Conditions

Preleukemia, historically a morphological and cytogenetic diagnosis, is now understood as a continuous clonal process in which somatic mutations, environmental influences, and stem cell pool dynamics interact over decades. Clonal hematopoiesis, the expansion of blood cells carrying somatic mutations, is near-universal in adults over age 70 and confers elevated risk of hematological malignancy, while also acting as a risk factor for cardiovascular and other age-related diseases. Here, we review the genetic and environmental factors that predispose to clonal expansion, organize the mechanisms of clonal expansion into three overlapping and interacting mechanisms (cell-autonomous fitness gain, context-conditional fitness, and nongenetic heritable states), and trace the trajectories that lead from clonal expansion to specific myeloid and lymphoid malignancies. We also discuss methods that have enabled mapping of clonal architecture in human tissue and close on the key questions that we anticipate will define the next decade of research in this field.