c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
By Anne Wilson, Mark J. Murphy, Thordur Oskarsson, Konstantinos Kaloulis, M. D. Bettess, G. Oser, A. Pasché, C. Knabenhans, H. Macdonald, A. Trumpp. Genes & Development, 2004
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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.
Subfields: Hematology, Immunology
View Paper: https://www.semanticscholar.org/paper/5132bbbdbcba41a29c2e5044c4cd98cad1e1a6d8
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Citations in the corpus
- Module map of stem cell genes guides creation of epithelial cancer stem cells. (2008, background): “…c-Myc promotes self-renewal and blocks differentiation in ESCs and cancer but, conversely, promotes differentiation with depletion of stem cells in hair bulge and bone marrow (Arnold and Watt, 2001; Arvanitis and Felsher, 2006; Cartwright et al., 2005; Waikel et al., 2001; Wilson et al., 2004).”
- Tumor heterogeneity: causes and consequences (2009, background): “In addition, oncogenic mutations that can trigger stronger proliferation without engaging intracellular tumor suppressors often result in loss of stemness [128,129], indicating additional, extrinsic tumor suppressor mechanisms.”
- Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation (2008, background): “C-Myc is another proliferative signal that can result in stem cell commitment, probably by inducing egress from the nich”
- MYC as a regulator of ribosome biogenesis and protein synthesis (2010, background): “The ability of MYC to coordinate ribosome biogenesis might be crucial for the orchestration of major physiological processes (such as proliferation, senescence, self-renewal and differentiation) that result in different cell fate”
- Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. (2009, positive): “BrdU staining was quantitated by flow cytometry ( Wilson et al., 2004 ) by combining surface staining to define each BM subset with intracellular staining us-”
- Bone-marrow haematopoietic-stem-cell niches (2006, background): “Indeed, continuous BrdU labelling has revealed a considerable number of cycling HSC”