Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 4, Pages 1050-1055Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1509333113
Keywords
childhood leukemia; somatic evolution; cancer; stochastic modeling; aging
Categories
Funding
- National Cancer Institute [R01CA180175]
- Linda Crnic Institute for Down Syndrome
- Leukemia Lymphoma Society
- St. Baldrick's Foundation
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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.
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