JAK2 V617F-positive polycythemia rubra vera maintained by approximately 18 stochastic stem cell divisions/year, explaining age of onest by a single rate-limiting mutation

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Abstract

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 (similar to 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".

Original languageEnglish
Pages (from-to)1675-1680
Number of pages6
JournalBlood
Volume110
Issue number5
Early online date23 Apr 2007
DOIs
Publication statusPublished - Sep 2007

Keywords

  • tyrosine kinase jak2
  • glycophorin-A locus
  • myeloproliferative disorders
  • hematopoietic stem
  • essential thrombocythemia
  • hodgkins-lymphoma
  • human cancer
  • carcinogenesis
  • identification
  • inactivation

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