Wilson A, Murphy MJ, Oskarsson T, Kaloulis K, Bettess MD, Oser GM et al.. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev 18: 2747-2763

Genetics and Stem Cell Laboratory, Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland.
Genes & Development (Impact Factor: 10.8). 12/2004; 18(22):2747-63. DOI: 10.1101/gad.313104
Source: PubMed


The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.

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Available from: Thordur Oskarsson, Mar 14, 2014
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    • "By interactions with these " blocks " of HSC niches, the progenitor cells derived from HSCs locating at the inner surface of BM migrate to blood vessels at the center of the BM cavity and then differentiate into mature cells. HSCs were hypothesized to be adhered to the surface of osteoblasts based on the observation of N-cadherin + cells at the endosteum that express some HSC markers [13] [14] [22]. By producing regulators such as angiopoietin [14] and osteopontin [18], they are able to regulate HSC pool size in vivo. "
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    ABSTRACT: Though discovered later than osteoblastic niche, vascular niche has been regarded as an alternative indispensable niche operating regulation on hematopoietic stem cells (HSCs). As significant progresses gained on this type niche, it is gradually clear that the main work of vascular niche is undertaking to support hematopoiesis. However, compared to what have been defined in the mechanisms through which the osteoblastic niche regulates hematopoiesis, we know less in vascular niche. In this review, based on research data hitherto we will focus on component foundation and various functions of vascular niche that guarantee the normal hematopoiesis process within bone marrow microenvironments. And the possible pathways raised by various research results through which this environment undergoes its function will be discussed as well.
    Full-text · Article · Apr 2014
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    • "Hematopoiesis is a highly organised system, tightly regulated by complex cell-niche (Wilson et al., 2004; Robb, 2007; Felli et al., 2010) and molecular interactions. The Class I homeobox (HOX) transcription factors that regulate normal development (Duboule and Dolle, 1989; Tschopp et al., 2009) are highly expressed in self-renewing HSC and progenitor (HSPC) pools (Pineault, et al., 2002; Dickson et al., 2009; Lebert et al., 2010) where malignant hematopoiesis originates (Lapidot et al., 1994; Bonnet and Dick, 1997; Reya et al., 2001; Hope et al., 2004). "
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    ABSTRACT: Background: Hematopoiesis is a paradigm for developmental processes, hierarchically organized, with stem cells at its origin. Hematopoietic stem cells (HSCs) replenish progenitor and precursor cells of multiple lineages, which normally differentiate into short-lived mature circulating cells. Hematopoiesis has provided insight into the molecular basis of tissue homeostasis and malignancy. Malignant hematopoiesis, in particular acute myeloid leukemia (AML), results from impaired development or differentiation of HSCs and progenitors. Co-overexpression of HOX and TALE genes, particularly the HOXA cluster and MEIS1, is associated with AML. Clinically relevant models of AML are required to advance drug development for an aging patient cohort. Results: Molecular analysis identified altered gene, microRNA, and protein expression in HOXA9/Meis1 leukemic bone marrow compared to normal controls. A candidate drug screen identified the c-Met inhibitor SU11274 for further analysis. Altered cell cycle status, apoptosis, differentiation, and impaired colony formation were shown for SU11274 in AML cell lines and primary leukemic bone marrow. Conclusions: The clonal HOXA9/Meis1 AML model is amenable to drug screening analysis. The data presented indicate that human AML cells respond in a similar manner to the HOXA9/Meis1 cells, indicating pre-clinical relevance of the mouse model.
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    • "However, whereas RNAi against Ncoa5 was initially efficient, the knockdown was unstable, and transcript levels recovered to normal as early as 4.5 dpc (Figure S7), indicating that more stable manipulations are required to uncover a role for Ncoa5 in mammalian embryonic development. Nonetheless, Ncoa5 is involved in the regulation of Estrogen Receptor alpha-mediated transcription (Sauvé et al., 2001; Zhang and Teng, 2001) and in the expression of c-Myc (Jiang et al., 2004), which has been implicated in the control of stem cell self-renewal (Cartwright et al., 2005; Wilson et al., 2004). In addition, the involvement of the Estrogen Receptor Esrrb and its coactivator Ncoa3 in the induction and maintenance of pluripotency (Feng et al., 2009) points toward a role for estrogenreceptor-mediated transcription in pluripotent stem cell function, possibly including additional regulation by Ncoa5. "
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    ABSTRACT: Planarian regeneration depends on the presence of pluripotent stem cells in the adult. We developed an in vivo stable isotope labeling by amino acids in cell culture (SILAC) protocol in planarians to identify proteins that are enriched in planarian stem cells. Through a comparison of SILAC proteomes of normal and stem cell-depleted planarians and of a stem cell-enriched population of sorted cells, we identified hundreds of stem cell proteins. One of these is an ortholog of nuclear receptor coactivator-5 (Ncoa5/CIA), which is known to regulate estrogen-receptor-mediated transcription in human cells. We show that Ncoa5 is essential for the maintenance of the pluripotent stem cell population in planarians and that a putative mouse ortholog is expressed in pluripotent cells of the embryo. Our study thus identifies a conserved component of pluripotent stem cells, demonstrating that planarians, in particular, when combined with in vivo SILAC, are a powerful model in stem cell research.
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