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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1675-1680. Prepublished online as a Blood First Edition Paper on April 23, 2007; DOI 10.1182/blood-2006-12-061911. This Article Full Text (PDF) Supplemental Appendix All Versions of this Article: blood-2006-12-061911v1 110/5/1675    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Vickers, M. A Search for Related Content PubMed PubMed Citation Articles by Vickers, M. A Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 7, 2006 Accepted April 18, 2007 JAK2 V617F positive polycythemia rubra vera maintained by ~18 stochastic stem cell divisions/year, explaining age of onset by a single rate limiting mutation Mark A Vickers* Department of Medicine & Therapeutics, Aberdeen University Medical School, Aberdeen, United Kingdom * Corresponding author; email: m.a.vickers{at}abdn.ac.uk. As the rates of most cancers are proportional to the 4-5th power of age ('log-log' behaviour), it is widely believed that 5-6 independent mutations are necessary for malignant transformation. Conversely, the peak incidences of most cancers are similar to stem cell mutation rates at single loci, implying only one rate limiting mutation. Here, flow cytometrically measured red blood cells mutated at a selectively neutral locus, glycophorin A, allow observation of individual stem cell differentiation events in a log-log malignancy, polycythemia rubra vera. Contrary to predictions from multistep models, the clone is driven by infrequent (<annual) and rare (~18 per year) differentiation events. These parameters imply that malignant stem cells have a modest selective advantage. Correspondingly minor, typically <20%, increases in stochastic self-renewal ratios are modelled to show that single mutations can result in the observed 4th power relationship with age. The conundrum between log-log behaviour and mutation rate is thereby reconcilable, with the age of onset arising not from the requirement for multiple, independent mutations but from infrequent, stochastic stem cell division rates and single mutations causing initially minor effects, but initiating a clone whose expected number increases successively with age - an 'exponential phenotype'. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Methuselah conundrum: MPDs in the elderly Peter J. Campbell and Anthony R. Green Blood 2007 110: 1409. [Full Text] [PDF] This article has been cited by other articles: A. Liso, F. Castiglione, A. Cappuccio, F. Stracci, R. F. Schlenk, S. Amadori, C. Thiede, S. Schnittger, P. J.M. Valk, K. Dohner, et al. A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1) Haematologica, August 1, 2008; 93(8): 1219 - 1226. [Abstract] [Full Text] [PDF]

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