To portray clonal evolution in blood cancer, count your stem cells

Abstract Clonal evolution, the process of expansion and diversification of mutated cells, plays an important role in cancer development, resistance, and relapse. Although clonal evolution is most often conceived of as driven by natural selection, recent studies uncovered that neutral evolution shapes clonal evolution in a significant proportion of solid cancers. In hematological malignancies, the interplay between neutral evolution and natural selection is also disputed. Because natural selection selects cells with a greater fitness, providing a growth advantage to some cells relative to others, the architecture of clonal evolution serves as indirect evidence to distinguish natural selection from neutral evolution and has been associated with different prognoses for the patient. Linear architecture, when the new mutant clone grows within the previous one, is characteristic of hematological malignancies and is typically interpreted as being driven by natural selection. Here, we discuss the role of natural selection and neutral evolution in the production of linear clonal architectures in hematological malignancies. Although it is tempting to attribute linear evolution to natural selection, we argue that a lower number of contributing stem cells accompanied by genetic drift can also result in a linear pattern of evolution, as illustrated by simulations of clonal evolution in hematopoietic stem cells. The number of stem cells contributing to long-term clonal evolution is not known in the pathological context, and we advocate that estimating these numbers in the context of cancer and aging is crucial to parsing out neutral evolution from natural selection, 2 processes that require different therapeutic strategies.