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

Elisa Laurenti, Barbara Varnum-Finney, Anne Wilson, Isabel Ferrero, William E. Blanco-Bose, Armin Ehninger, Paul S Knoepfler, Pei Feng Cheng, H. Robson MacDonald, Robert N. Eisenman, Irwin D. Bernstein, Andreas Trumpp

Research output: Contribution to journalArticle

168 Scopus citations

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 GranzymeB, 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.

Original languageEnglish (US)
Pages (from-to)611-624
Number of pages14
JournalCell Stem Cell
Volume3
Issue number6
DOIs
StatePublished - Dec 4 2008
Externally publishedYes

Keywords

  • STEMCELL

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

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    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. (2008). Hematopoietic Stem Cell Function and Survival Depend on c-Myc and N-Myc Activity. Cell Stem Cell, 3(6), 611-624. https://doi.org/10.1016/j.stem.2008.09.005