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Cited by 305Hematopoietic Stem Cell TransplantationMesenchymal stem cell researchBlood disorders and treatments

Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity

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Laurenti, Elisa, Varnum-Finney, Barbara, Wilson, Anne, Ferrero, Isabel, Blanco-Bose, William E., Ehninger, Armin, Knoepfler, Paul S., Cheng, Pei-Feng +4 more·2008·Cell Stem Cell
DOI 10.1016/j.stem.2008.09.005PMC PMC2635113
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Abstract

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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  • IL-1 downregulates expression of Myc, a crucial upstream regulator of protein synthesis and cell cycle genes that leads to defective cell cycle entry if deleted in stem cells.

    “Likewise, IL-1 downregulates expression of Myc, a crucial upstream regulator of protein synthesis and cell cycle genes that leads to defective cell cycle entry if deleted in stem cells (Laurenti et al., 2008; Scognamiglio et al., 2016; Wilson et al., 2004).”

    From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Laurenti et al., 2008

    The Results section reports that hematopoietic stem cells lacking both c-Myc and N-Myc cycled significantly more than controls, contrary to the claim that deletion causes defective cell-cycle entry in stem cells. The paper does support a role for Myc in protein synthesis: the Results report downregulation of 31 ribosomal-protein genes after deletion. The cited passages do not address IL-1 regulation of Myc. (LLM, conf=0.88)

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Authors
Laurenti, E., Varnum-Finney, B., Wilson, A., Ferrero, I., Blanco-Bose, W. E., Ehninger, A., Knoepfler, P. S., Cheng, P.-F., MacDonald, H. R., Eisenman, R. N., Bernstein, I. D., & Trumpp, A.
Affiliations
  • École Polytechnique Fédérale de Lausanne (CH)
  • Ludwig Cancer Research (CH)
  • Fred Hutch Cancer Center (US)
  • German Cancer Research Center (DE)
Corresponding author
Trumpp, Andreas
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2008-12
Volume
3
Issue
6
Pages
611-624
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2008.09.005
PMC
PMC2635113
OpenAlex
W2048768497
Cited by
305
References
4
Citations by year
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FWCI
12.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • IRIS (submittedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
Funders
  • National Science Foundation
  • École Polytechnique Fédérale de Lausanne
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (P01HL084205)
  • National Cancer Institute (R01CA020525, R01-CA20525)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
Keywords
hematopoietic stem cells, c-Myc, MYCN, MYC gene, stem cell self-renewal, stem cell differentiation, stem cell proliferation, stem cell apoptosis, granzyme B, pancytopenia, conditional gene deletion, hematopoiesis
MeSH terms
Animals, Cell Differentiation, Cell Survival, Cells, Cultured, Graft Survival, Hematopoiesis, Hematopoietic Stem Cells, Pancytopenia, Stress, Physiological, Signal Transduction, Proto-Oncogene Proteins c-myc, Mice, Knockout, Hematopoietic Stem Cell Transplantation, Cell Lineage, Cell Proliferation, Mice, Granzymes

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