Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells

Ömer H. Yilmaz, Riccardo Valdez, Brian K. Theisen, Wei Guo, David O. Ferguson, Hong Wu and Sean J. Morrison ()
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Ömer H. Yilmaz: University of Michigan
Riccardo Valdez: University of Michigan
Brian K. Theisen: University of Michigan
Wei Guo: Molecular and Medical Pharmacology, UCLA School of Medicine
David O. Ferguson: University of Michigan
Hong Wu: Molecular and Medical Pharmacology, UCLA School of Medicine
Sean J. Morrison: University of Michigan

Nature, 2006, vol. 441, issue 7092, 475-482

Abstract: Abstract Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.

Date: 2006
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DOI: 10.1038/nature04703

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