Hematopoietic Stem Cell Function and Survival Depend on c-Myc and N-Myc Activity

Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC, Swiss Institute for Experimental Cancer Research, School of Life Science, CH-1066 Epalinges, Switzerland.
Cell stem cell (Impact Factor: 22.27). 01/2009; 3(6):611-24. DOI: 10.1016/j.stem.2008.09.005
Source: PubMed


Myc activity is emerging as a key element in acquisition and maintenance of stem cell properties. We have previously shown that c-Myc deficiency results in accumulation of defective hematopoietic stem cells (HSCs) due to niche-dependent differentiation defects. Here we report that immature HSCs coexpress c-myc and N-myc mRNA at similar levels. Although conditional deletion of N-myc in the bone marrow does not affect hematopoiesis, combined deficiency of c-Myc and N-Myc (dKO) results in pancytopenia and rapid lethality. Interestingly, proliferation of HSCs depends on both myc genes during homeostasis, but is c-Myc/N-Myc independent during bone marrow repair after injury. Strikingly, while most dKO hematopoietic cells undergo apoptosis, only self-renewing HSCs accumulate the cytotoxic molecule Granzyme B, normally employed by the innate immune system, thereby revealing an unexpected mechanism of stem cell apoptosis. Collectively, Myc activity (c-Myc and N-Myc) controls crucial aspects of HSC function including proliferation, differentiation, and survival.

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Available from: Elisa Laurenti, Apr 04, 2014
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    • "Rbbp4, also called as RBAP46/48, is identified as a subunit of the NURF complex (Song et al., 2009; Alkhatib and Landry, 2011), but it is also associated with the NuRD or the Sin3 complex (Kuzmichev et al., 2002; Lejon et al., 2011). A previous study reported that c-Myc exists in both LT-HSCs and MPPs (Laurenti et al., 2008). Here we showed that c-Myc expression is dependent on WASH and the NURF complex in LT-HSCs. "
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    ABSTRACT: Hematopoiesis is fully dependent on hematopoietic stem cells (HSCs) that possess the capacity to self-renew and differentiate into all blood cell lineages. WASH, Wiskott-Aldrich syndrome protein (WASP) and SCAR homologue (WASH) is involved in endosomal sorting as an actin-nucleating protein. Here, we show that conditional WASH deletion in the hematopoietic system causes defective blood production of the host, leading to severe cytopenia and rapid anemia. WASH deficiency causes the accumulation of long-term (LT)-HSCs in bone marrow and perturbs their differentiation potential to mature blood lineages. Importantly, WASH is located in the nucleus of LT-HSCs and associates with the nucleosome remodeling factor (NURF) complex. WASH assists the NURF complex to the promoter of c-Myc gene through its VCA domain-dependent nuclear actin nucleation. WASH deletion suppresses the transcriptional activation of c-Myc gene and impairs the differentiation of LT-HSCs. WASH acts as an upstream regulator to modulate c-Myc transcription for hematopoietic regulation.
    The Journal of Cell Biology 09/2014; 211(10). DOI:10.1084/jem.20140169 · 9.83 Impact Factor
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    • "First, we compared the gene expression between Max-null ESCs and c-Myc/N-Myc dKO HSCs. However, we did not find any obvious tendency that the genes regulated differentially in dKO HSCs compared with those in wild-type HSCs (Laurenti et al., 2008) altered their expression levels in a similar trend in Max-null ESCs (Figures S2A and S2B), indicating that gene sets regulated by Myc/Max complexes are rather different between ESCs and HSCs. As a next step, the genes with altered expression levels more than 2-fold (upregulated genes, 1696; downregulated genes, 1402) in Max-null ESCs were assigned to gene ontology (GO) classification to correlate gene expression changes with overall molecular functions. "
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    • "c-Myc regulates cellular proliferation, metabolism, and maintenance of progenitor populations7,8 and globally amplifies transcription by direct interactions with RNA polymerases I, II and III, accounting for its regulation of disparate and context-dependent target loci across cell types9-11. Forced expression of L-Myc exerts weaker effects than c-Myc for cell growth, apoptosis and transformation12 but is more efficient in reprogramming fibroblasts toward induced pluripotent stem cells13. "
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    ABSTRACT: The transcription factors c-Myc and N-Myc-encoded by Myc and Mycn, respectively-regulate cellular growth and are required for embryonic development. A third paralogue, Mycl1, is dispensable for normal embryonic development but its biological function has remained unclear. To examine the in vivo function of Mycl1 in mice, we generated an inactivating Mycl1(gfp) allele that also reports Mycl1 expression. We find that Mycl1 is selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression is initiated in the common DC progenitor concurrent with reduction in c-Myc expression. Mature DCs lack expression of c-Myc and N-Myc but maintain L-Myc expression even in the presence of inflammatory signals such as granulocyte-macrophage colony-stimulating factor. All DC subsets develop in Mycl1-deficient mice, but some subsets such as migratory CD103(+) conventional DCs in the lung and liver are greatly reduced at steady state. Importantly, loss of L-Myc by DCs causes a significant decrease in in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming.
    Nature 02/2014; 507(7491). DOI:10.1038/nature12967 · 41.46 Impact Factor
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