Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells

Nature. 2006 May 25;441(7092):475-82. doi: 10.1038/nature04703. Epub 2006 Apr 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cell Proliferation
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism*
  • Leukemia / genetics
  • Leukemia / metabolism*
  • Leukemia / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Protein Kinases / metabolism
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases

Substances

  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Sirolimus