PTEN-dependence distinguishes haematopoietic stem cells from leukemia-initating cells

Howard Hughes Medical Institute, Life Sciences Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
Nature (Impact Factor: 41.46). 06/2006; 441(7092):475-82. DOI: 10.1038/nature04703
Source: PubMed

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.

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Available from: Brian Theisen, Aug 09, 2015
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    • "Activation of AKT in hematopoiesis as induced experimentally by deletion of Pten leads to a myeloproliferative syndrome and eventual loss of hematopoietic stem cells (Kharas et al., 2010; Yilmaz et al., 2006; Zhang et al., 2006). This is mTOR dependent, as loss of hematopoietic stem cells can be rescued by rapamycin. "
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    Stem Cell Reports 11/2014; 3(5). DOI:10.1016/j.stemcr.2014.08.011 · 5.37 Impact Factor
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    • "As a Rheb GAP, TSC1/2 negatively regulates mTORC1 activity by converting GTP-bound Rheb into its inactive GDP-bound state. Initially, it was reported that deletion of phosphatase and tensin homologue (Pten), a negative regulator of the PI3K–Akt pathway, from HSCs in adult mice promotes HSC proliferation, resulting in HSC depletion and leukemic transformation (Yilmaz et al., 2006; Zhang et al., 2006). The effect of Pten deletion on HSCs could be ameliorated by the treatment with rapamycin, indicating that mTORC1 is involved in regulation of HSCs. "
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    Advances in Cancer Research 06/2014; 122C:1-67. DOI:10.1016/B978-0-12-420117-0.00001-3 · 5.32 Impact Factor
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    • "Regardless of these differences, SC proliferation is tightly regulated to suit the homeostatic needs of their respective tissues, and disruption of this regulation can lead to severe consequences. For example, mutations causing hematopoietic stem cells (HSCs) to hyperproliferate often lead to their exhaustion (Pietras et al., 2011; Yilmaz et al., 2006), whereas mutations causing insufficient SC activity in HFs results in a failure to regrow the hair coat after rounds of regeneration (Chen et al., 2012). Elucidating how SC proliferation is governed and delineating the impact of niche components on this process therefore become critical. "
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