Elevated incidence of childhood leukemia relative to young adult ages is difficult to explain from the standpoint of oncogenic mutation accumulation. We applied a stochastic Monte Carlo model of hematopoietic stem cell (HSC) clonal dynamics based on published age-dependent parameters of HSCs. Our modeling results demonstrate that childhood and adult HSC clonal dynamics differ by the factors that determine the number of cell divisions per clonal context. Late in life, positive selection leading to clonal expansions increases the number of cell divisions per clone, whereas in childhood a similar increase is achieved by the much higher HSC division frequencies and drift-affected clonal expansions. We provide a mathematical argument that the obtained clonal dynamics and cell division measurements can explain the age-dependent incidence of leukemia.

Abstract

Young children have higher rates of leukemia than young adults. This fact represents a fundamental conundrum, because hematopoietic cells in young children should have fewer mutations (including oncogenic ones) than such cells in adults. Here, we present the results of stochastic modeling of hematopoietic stem cell (HSC) clonal dynamics, which demonstrated that early HSC pools were permissive to clonal evolution driven by drift. We show that drift-driven clonal expansions cooperate with faster HSC cycling in young children to produce conditions that are permissive for accumulation of multiple driver mutations in a single cell. Later in life, clonal evolution was suppressed by stabilizing selection in the larger young adult pools, and it was driven by positive selection at advanced ages in the presence of microenvironmental decline. Overall, our results indicate that leukemogenesis is driven by distinct evolutionary forces in children and adults.