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Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells

Author

Listed:
  • 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)

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.

Suggested Citation

  • Ömer H. Yilmaz & Riccardo Valdez & Brian K. Theisen & Wei Guo & David O. Ferguson & Hong Wu & Sean J. Morrison, 2006. "Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells," Nature, Nature, vol. 441(7092), pages 475-482, May.
    • Handle: RePEc:nat:nature:v:441:y:2006:i:7092:d:10.1038_nature04703
    DOI: 10.1038/nature04703
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