p53 Regulates Hematopoietic Stem Cell Quiescence

Molecular Phamacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Cell stem cell (Impact Factor: 22.27). 02/2009; 4(1):37-48. DOI: 10.1016/j.stem.2008.11.006
Source: PubMed


The importance of the p53 protein in the cellular response to DNA damage is well known, but its function during steady-state hematopoiesis has not been established. We have defined a critical role of p53 in regulating hematopoietic stem cell quiescence, especially in promoting the enhanced quiescence seen in HSCs that lack the MEF/ELF4 transcription factor. Transcription profiling of HSCs isolated from wild-type and p53 null mice identified Gfi-1 and Necdin as p53 target genes, and using lentiviral vectors to upregulate or knockdown the expression of these genes, we show their importance in regulating HSC quiescence. Establishing the role of p53 (and its target genes) in controlling the cell-cycle entry of HSCs may lead to therapeutic strategies capable of eliminating quiescent cancer (stem) cells.

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    • "Tight regulation of quiescence is essential, since failure to exit quiescence will prevent tissue regeneration while loss of quiescence might lead to exhaustion of the stem cell pool compromising long-term tissue maintenance (Chakkalakal et al., 2012; Cheung and Rando, 2013). Various mechanisms have been implicated in the molecular regulation of stem cell quiescence, foremost processes depending on p53 (Liu et al., 2009), Rb (Hosoyama et al., 2011), CDK inhibitors (Cheng et al., 2000; Kippin et al., 2005), notch signaling (Bjornson et al., 2012), miRNAs (Cheung et al., 2012), and PRC2 (polycomb )-dependent chromatin modifications (Juan et al., 2011). "
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    ABSTRACT: Skeletal muscle stem cells (MuSCs) are required for regeneration of adult muscle following injury, a response that demands activation of mainly quiescent MuSCs. Despite the need for dynamic regulation of MuSC quiescence, relatively little is known about the determinants of this property. Here, we show that Suv4-20h1, an H4K20 dimethyltransferase, controls MuSC quiescence by promoting formation of facultative heterochromatin (fHC). Deletion of Suv4-20h1 reduces fHC and induces transcriptional activation and repositioning of the MyoD locus away from the heterochromatic nuclear periphery. These effects promote MuSC activation, resulting in stem cell depletion and impaired long-term muscle regeneration. Genetic reduction of MyoD expression rescues fHC formation and lost MuSC quiescence, restoring muscle regeneration capacity in Suv4-20h1 mutants. Together, these findings reveal that Suv4-20h1 actively regulates MuSC quiescence via fHC formation and control of the MyoD locus, thereby guarding and preserving the stem cell pool over a lifetime.
    Full-text · Article · Dec 2015 · Cell stem cell
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    • "First, CML arises from a normal pluripotent stem cell, which lacks expression of relevant functional levels of p53, because in stem cells, p53 negatively regulates self-renewability, quiescence [62–65] and pluripotency by reprogramming [66]. Secondly, polycomb repressor complexes epigenetically silence the Cdkn2a/b gene cluster (encoding INK-4A/ARF) in hematopoietic stem cells. "
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    ABSTRACT: Deregulated BCR-ABL oncogenic activity leads to transformation, oncogene addiction and drives disease progression in chronic myeloid leukemia (CML). Inhibition of BCR-ABL using Abl-specific kinase inhibitors (TKI) such as imatinib induces remarkable clinical responses. However, approximately only less than 15 % of all chronic-phase CML patients will remain relapse-free after discontinuation of imatinib in deep molecular remission. It is not well understood why persisting CML cells survive under TKI therapy without developing clonal evolution and frank TKI resistance. BCR-ABL expression level may be critically involved. Whereas higher BCR-ABL expression has been described as a pre-requisite for malignant CML stem cell transformation and CML progression to blast crisis, recent evidence suggests that during persistence TKI select for CML precursors with low BCR-ABL expression. Genetic, translational and clinical evidence is discussed to suggest that TKI-induced maintenance of low BCR-ABL signaling output may be potently tumor suppressive, because it abrogates oncogenic addiction.
    Preview · Article · Feb 2014 · Current Hematologic Malignancy Reports
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    • "HSCs in old mice lacking p16 have increased regenerative potential, suggesting that p16 plays a critical role in limiting HSC selfrenewal (Janzen et al., 2006). In p53-null mice, the number of HSCs increases and they perform better in competitive repopulation, suggesting an enhanced self-renewal capacity (TeKippe et al., 2003; Liu et al., 2009). Moreover, mice with one wild-type allele and one mutant allele of p53 that lacks the N-terminal transactivation domain maintain cancer protection, but age prematurely including impairment of HSCs (Tyner et al., 2002; Maier et al., 2004; Dumble et al., 2007). "
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    ABSTRACT: The age-dependent decline in the self-renewal capacity of stem cells plays a critical role in aging, but the precise mechanisms underlying this decline are not well understood. By limiting proliferative capacity, senescence is thought to play an important role in age-dependent decline of stem cell self-renewal, although direct evidence supporting this hypothesis is largely lacking. We have previously identified the E3 ubiquitin ligase Smurf2 as a critical regulator of senescence. In this study, we found that mice deficient in Smurf2 had an expanded hematopoietic stem cell (HSC) compartment in bone marrow under normal homeostatic conditions, and this expansion was associated with enhanced proliferation and reduced quiescence of HSCs. Surprisingly, increased cycling and reduced quiescence of HSCs in Smurf2-deficient mice did not lead to premature exhaustion of stem cells. Instead, HSCs in aged Smurf2-deficient mice had a significantly better repopulating capacity than aged wild-type HSCs, suggesting that decline in HSC function with age is Smurf2 dependent. Furthermore, Smurf2-deficient HSCs exhibited elevated long-term self-renewal capacity and diminished exhaustion in serial transplantation. As we found that the expression of Smurf2 was increased with age and in response to regenerative stress during serial transplantation, our findings suggest that Smurf2 plays an important role in regulating HSC self-renewal and aging.
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