title: Stochastic modeling reveals an evolutionary mechanism underlying elevated rates of childhood 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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Andrii I
authors.initials: AI
authors.lastname: Rozhok
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Salstrom
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045; Integrated Department of Immunology, University of Colorado School of Medicine, Aurora, CO 80045; Section of Hematology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045; Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO 80045 james.degregori@ucdenver.edu.
authors.forename: James
authors.initials: J
authors.lastname: DeGregori
mesh_terms: D000367:Age Factors; D002648:Child; D060965:Clonal Evolution; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000209:etiology*; D009154:Mutation; D013269:Stochastic Processes
keywords: aging; cancer; childhood leukemia; somatic evolution; stochastic modeling