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 in | Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 4; pp. 1050 - 1055 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
26.01.2016
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 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 |