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Blood, 15 October 2005, Vol. 106, No. 8, pp. 2688-2692.
Prepublished online as a Blood First Edition Paper on July 7, 2005; DOI 10.1182/blood-2005-03-1240.
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Submitted March 28, 2005
Accepted June 8, 2005
The kinetics of clonal dominance in myeloproliferative disorders
Sandra N Catlin, Peter Guttorp, and Janis L Abkowitz*
Department of Mathematical Sciences, University of Nevada, Las Vegas, NV, USA
Departments of Statistics and Medicine, University of Washington, Seattle, WA, USA
* Corresponding author; email: janabk{at}u.washington.edu.
To study the clonal evolution in myeloproliferative disorders, we used stochastic models of hematopoiesis for mouse and cat, species for which the in vivo kinetics of hematopoietic stem cells (HSC) have been experimentally defined. We determined the consequence if one HSC became able to survive without the support of a microenvironmental niche, while its other behavior did not change. Neoplastic cells persisted and dominated hematopoiesis in 14% of mice and 17% of cats (requiring mean times of 2.5±0.5 and 7.0±1.2 years, respectively (n=1000 simulations/species)). In both species, when the number of neoplastic HSC exceeded 0.5% of all HSC, clonal dominance was inevitable. Our results can explain the absence of clonal myeloproliferative disorders in mice (lifetime two years), are consistent with clinical observations in cats and provide insight into the progression of chronic myelogenous leukemia (CML) in persons. They also demonstrate that competition for microenvironmental support can lead to a suppression of normal hematopoiesis as neoplasia evolves. A toxic or immunologic suppression of normal HSC is not required.
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