Stochastic modeling reveals an evolutionary mechanism underlying elevated rates of childhood leukemia

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 hematop...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 113; no. 4; pp. 1050 - 1055
Main Authors Rozhok, Andrii I., Salstrom, Jennifer L., DeGregori, James
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 26.01.2016
National Acad Sciences
Subjects
Age Factors
Biological Sciences
Child
Child development
Children & youth
Clonal Evolution
Evolution
Hematopoietic Stem Cells - physiology
Humans
Leukemia
Leukemia - etiology
Mutation
Stochastic models
Stochastic Processes
Young adults
stochastic modeling
cancer
aging
childhood leukemia
somatic evolution
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Summary: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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Edited by Brian J. Druker, Oregon Health & Science University Knight Cancer Institute, Portland, OR, and approved December 11, 2015 (received for review May 13, 2015)
Author contributions: A.I.R., J.L.S., and J.D. designed research; A.I.R. performed research; and A.I.R., J.L.S., and J.D. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1509333113