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


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

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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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    ABSTRACT: Central to cellular proliferative, survival, and metabolic responses is the serine/threonine kinase mTOR, which is activated in many human cancers. mTOR is present in distinct complexes that are either modulated by AKT (mTORC1) or are upstream and regulatory of it (mTORC2). Governance of mTORC2 activity is poorly understood. Here, we report a transmembrane molecule in hematopoietic progenitor cells that physically interacts with and inhibits RICTOR, an essential component of mTORC2. Upstream of mTORC2 (UT2) negatively regulates mTORC2 enzymatic activity, reducing AKT(S473), PKC?, and NDRG1 phosphorylation and increasing FOXO transcriptional activity in an mTORC2-dependent manner. Modulating UT2 levels altered animal survival in a T cell acute lymphoid leukemia (T-ALL) model that is known to be mTORC2 sensitive. These studies identify an inhibitory component upstream of mTORC2 in hematopoietic cells that can reduce mortality from NOTCH-induced T-ALL. A transmembrane inhibitor of mTORC2 may provide an attractive target to affect this critical cell regulatory pathway.
    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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    ABSTRACT: Reactive oxygen species (ROS) play an important role in determining the fate of normal stem cells. Low levels of ROS are required for stem cells to maintain quiescence and self-renewal. Increases in ROS production cause stem cell proliferation/differentiation, senescence, and apoptosis in a dose-dependent manner, leading to their exhaustion. Therefore, the production of ROS in stem cells is tightly regulated to ensure that they have the ability to maintain tissue homeostasis and repair damaged tissues for the life span of an organism. In this chapter, we discuss how the production of ROS in normal stem cells is regulated by various intrinsic and extrinsic factors and how the fate of these cells is altered by the dysregulation of ROS production under various pathological conditions. In addition, the implications of the aberrant production of ROS by tumor stem cells for tumor progression and treatment are also discussed.
    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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    • "Importantly, the authors show that inhibition of mTOR signaling with rapamycin restores HSC function and impairs the generation and maintenance of LSCs, demonstrating in this way that it is possible to target LSCs without affecting normal hematopoiesis and stem cell function (Yilmaz, Valdez, 2006). Moreover, HSC depletion appears to result not from induced cell death but rather from inhibition of self-renewal upon loss of Pten (Yilmaz, Valdez, 2006). Concurring with these results, Zhang and colleagues demonstrated that ablation of Pten in bone marrow cells leads to the decline of long-term HSCs as a result of aberrantly increased levels of cycling HSCs (Zhang, Grindley, 2006). "
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    ABSTRACT: Leukemia stem cells (LSCs) are considered responsible for leukemia initiation, relapse and resistance to chemotherapy. These cells have self-renewal capacity and originate the other cells in the leukemia pool. Therefore, in order to completely eradicate leukemia cells and consequently cure the disease, therapies should in principle necessarily target LSCs. However, the fact that LSCs share functional and phenotypic properties with normal hematopoietic stem cells (HSCs) poses a significant challenge: how to target LSCs without damaging normal HSCs and compromising hematopoiesis? The discovery that PTEN regulates LSCs and HSCs through different mechanisms, demonstrated that it is possible to identify pathways that differentially impact leukemia and normal stem cell function and opened new therapeutic perspectives for the selective elimination of LSCs. In this review, we briefly discuss the mechanisms that regulate PTEN function in LSCs and HSCs and their potential for the development of LSC-targeted therapies.
    Advances in Biological Regulation 06/2014; 56. DOI:10.1016/j.jbior.2014.05.005
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