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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.
NEOPLASIA JAK2 617V>F–positive polycythemia rubra vera maintained by approximately 18 stochastic stem-cell divisions per year, explaining age of onset by a single rate-limiting mutation1 Department of Medicine and Therapeutics, Aberdeen University Medical School, Aberdeen, United Kingdom
As the rates of most cancers are proportional to the fourth to fifth power of age ("log-log" behavior), it is widely believed that 5 to 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 (
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
18 per year) differentiation events. These parameters imply that malignant stem cells have a modest selective advantage. Correspondingly minor, typically less than 20%, increases in stochastic self-renewal ratios are modeled to show that single mutations can result in the observed fourth power relationship with age. The conundrum between log-log behavior 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." 
