p53-Mediated Hematopoietic Stem and Progenitor Cell Competition

Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Cell stem cell (Impact Factor: 22.27). 04/2010; 6(4):309-22. DOI: 10.1016/j.stem.2010.03.002
Source: PubMed


Cell competition was originally described in Drosophila as a process for selection of the fittest cells. It is likely to play an important role in tissue homeostasis in all metazoans, but little is known about its role and regulation in mammals. By using genetic mosaic mouse models and bone marrow chimeras, we describe here a form of cell competition that selects for the least damaged cells. This competition is controlled by p53 but is distinct from the classical p53-mediated DNA damage response: it persists for months, is specific to the hematopoietic stem and progenitor cells, and depends on the relative rather than absolute level of p53 in competing cells. The competition appears to be mediated by a non-cell-autonomous induction of growth arrest and senescence-related gene expression in outcompeted cells with higher p53 activity. p53-mediated cell competition of this type could potentially contribute to the clonal expansion of incipient cancer cells.

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    • "Similarly, cell competition has been observed between wild-type cells and cells overexpressing myc in the mouse heart (Villa del Campo et al., 2014). In addition, this phenomenon has been observed in some adult niche compartments (Jin et al., 2008; Issigonis et al., 2009; Rhiner et al., 2009; Bondar and Medzhitov, 2010; Marusyk et al., 2010), and a recent report suggests that it may also be taking place in adult fly tissues (Merino et al., 2015). However , how cell competition affects adult tissue dynamics and stem cell behavior has been little explored so far. "
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    ABSTRACT: Throughout their lifetime, cells may suffer insults that reduce their fitness and disrupt their function, and it is unclear how these potentially harmful cells are managed in adult tissues. We address this question using the adult Drosophila posterior midgut as a model of homeostatic tissue and ribosomal Minute mutations to reduce fitness in groups of cells. We take a quantitative approach combining lineage tracing and biophysical modeling and address how cell competition affects stem cell and tissue population dynamics. We show that healthy cells induce clonal extinction in weak tissues, targeting both stem and differentiated cells for elimination. We also find that competition induces stem cell proliferation and self-renewal in healthy tissue, promoting selective advantage and tissue colonization. Finally, we show that winner cell proliferation is fueled by the JAK-STAT ligand Unpaired-3, produced by Minute(-/+) cells in response to chronic JNK stress signaling. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Developmental Cell 07/2015; 34(3). DOI:10.1016/j.devcel.2015.06.010 · 9.71 Impact Factor
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    • "Namely, TP53 loss favors symmetric divisions and increases progenitor reprogramming. Moreover, as TP53-mutated HSC clones were described to gain a selective advantage in DNA-damage conditions, TP53-mediated competition may play a role in the early stages of leukemia as well as in its progression [Liu et al., 2009; Bondar and Medzhitov, 2010; Bonizzi et al., 2012]. Although pathologic changes in HSC compartment behavior have also been described in CLL, this mature B-cell neoplasm likely transforms from an as yet unknown subtype of differentiated B-lymphocytes [Kikushige et al., 2011; García-Muñoz et al., 2012; Seifert et al., 2012]. "
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    ABSTRACT: In leukemia, TP53 mutations are not frequent but clearly associate with impaired survival and therapy response. Here we describe the biological and clinical consequences of TP53 dysfunction as well as the methodical aspects of TP53 analysis in chronic lymphocytic leukemia (CLL). In CLL, TP53 defects are routinely analyzed as part of disease prognostication. Deletions of TP53 locus (17p) have been uniformly detected using I-FISH for several years. Since monoallelic mutations have also been shown to have negative prognostic impact, it is also recommended to examine TP53 mutations. Several methods are used to detect TP53 mutations and next-generation sequencing (NGS) is becoming a convenient option for routine analysis. Besides this, ultra-deep NGS permits the detection of minor clones carrying TP53 mutations, even below 1%. The prognostic impact of minor TP53-defective subclones is currently unknown, nevertheless they unequivocally bear the risk of being selected by therapy. Prospective studies assessing the consequences of carrying such clones are in progress. This article is protected by copyright. All rights reserved.
    Human Mutation 06/2014; 35(6). DOI:10.1002/humu.22508 · 5.14 Impact Factor
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    • "Here, the relative cellular level of the tumor suppressor p53 dictates the direction of competition, and this is dependent on the presence of both HSPC populations. Cells with higher p53 activity induce the senescence program only when in mixed company with low-p53 cells (Bondar and Medzhitov 2010). "
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    ABSTRACT: Studies in Drosophila and mammals have made it clear that genetic mutations that arise in somatic tissues are rapidly recognized and eliminated, suggesting that cellular fitness is tightly monitored. During development, damaged, mutant, or otherwise unfit cells are prevented from contributing to the tissue and are instructed to die, whereas healthy cells benefit and populate the animal. This cell selection process, known as cell competition, eliminates somatic genetic heterogeneity and promotes tissue fitness during development. Yet cell competition also has a dark side. Super competition can be exploited by incipient cancers to subvert cellular cooperation and promote selfish behavior. Evidence is accumulating that MYC plays a key role in regulation of social behavior within tissues. Given the high number of tumors with deregulated MYC, studies of cell competition promise to yield insight into how the local environment yields to and participates in the early stages of tumor formation.
    Cold Spring Harbor Perspectives in Medicine 04/2014; 4(4). DOI:10.1101/cshperspect.a014274 · 9.47 Impact Factor
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