Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Poor competition in hematopoietic stem/progenitor pools favors tumorigenesis


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Decreased cell cycle progression during hematopoiesis and reduced blood cell production can be associated with increased tumorigenesis, such as in E2F1/E2F2 mutant mice, people with inadequate folate intake, and during particular chemotherapeutic regimens. We propose a hypothesis whereby reduced proliferation of blood progenitors selects for oncogenic mutations that improve cell cycle progression. Basically, impeded proliferation of progenitor cells provides for poor competition, promoting the expansion of progenitors that acquire oncogenic mutations. As cancer development has clear attributes reminiscent of Darwinian evolution, it is perhaps not surprising that it should become easier for a mutant cell clone to be the fittest as the quality of the competition declines. Contexts which involve nucleotide deprivation and DNA damage, and thus impeded DNA replication, often enhance mutation accumulation, and we propose that mutator phenotypes synergize with poor competition to promote tumorigenesis. We suggest that the poorly competitive progenitor environments that result from folate deficiency, particular inherited polymorphisms, and certain chemotherapeutic treatments contribute to increased cancer risk in affected people. To test our hypothesis, we will introduce the oncogenic Bcr-Abl and E2a-Hlf translocation products into mouse BM stem cells using retroviral transduction, and then reconstitute hematopoiesis in recipient mice using these stem cells. We will ask how genetic, dietary and chemotherapeutic contexts that impair cell cycle progression in blood progenitor cells affect the ability of oncogene expressing cells to competitively expand and contribute to leukemogenesis. We will also investigate the mechanism whereby each oncogene improves cell proliferation in compromised progenitors, such as by bypassing checkpoints and restoring DNA synthesis. We anticipate that particular conditions that impair S phase progression will promote the expansion and tumorigenicity of oncogene expressing progenitor cells. These studies should define novel factors governing tumorigenesis, and will create unique model systems that could suggest further epidemiological studies in humans.


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R01CA109657

Collapse Time 
Collapse start date
2005-09-13
Collapse end date
2011-06-30

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