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IFNα activates dormant haematopoietic stem cells in vivo

Nature volume 458, pages 904–908 (2009)Cite this article

Abstract

Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. After injury these cells are induced to proliferate to quickly re-establish homeostasis1. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-α (IFNα), HSCs efficiently exit G0 and enter an active cell cycle. HSCs respond to IFNα treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFNα target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFNα/β receptor (IFNAR)2, STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFNα stimulation, demonstrating that STAT1 and Sca-1 mediate IFNα-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil1,5, HSCs pre-treated (primed) with IFNα and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFNα are functionally compromised and are rapidly out-competed by non-activatable Ifnar-/- cells in competitive repopulation assays. Whereas chronic activation of the IFNα pathway in HSCs impairs their function, acute IFNα treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNα on leukaemic cells6,7, and raise the possibility for new applications of type I interferons to target cancer stem cells8.

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Figure 1: IFNα induces efficient cell cycle entry of dormant HSCs in vivo.
Figure 2: A direct effect on HSCs, combined with an indirect mechanism, promotes HSC proliferation in response to IFNα in vivo.
Figure 3: IFNα-activated HSCs upregulate and are dependent on STAT1 and Sca-1 signalling.
Figure 4: Priming of IFNα followed by 5-FU treatment or chronic IFNα stimulation causes HSC loss.

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Gene Expression Omnibus

Data deposits

The microarray data have been deposited in the NCBI Gene Expression Omnibus (GEO) and are accessible through GEO series accession number GSE14361.

References

  1. Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008)

    Article  CAS  Google Scholar 

  2. Muller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994)

    Article  ADS  CAS  Google Scholar 

  3. Durbin, J. E., Hackenmiller, R., Simon, M. C. & Levy, D. E. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84, 443–450 (1996)

    Article  CAS  Google Scholar 

  4. Ito, C. Y., Li, C. Y., Bernstein, A., Dick, J. E. & Stanford, W. L. Hematopoietic stem cell and progenitor defects in Sca-1/Ly-6A-null mice. Blood 101, 517–523 (2003)

    Article  CAS  Google Scholar 

  5. Randall, T. D. & Weissman, I. L. Phenotypic and functional changes induced at the clonal level in hematopoietic stem cells after 5-fluorouracil treatment. Blood 89, 3596–3606 (1997)

    CAS  PubMed  Google Scholar 

  6. Kujawski, L. A. & Talpaz, M. The role of interferon-α in the treatment of chronic myeloid leukemia. Cytokine Growth Factor Rev. 18, 459–471 (2007)

    Article  CAS  Google Scholar 

  7. Hehlmann, R., Hochhaus, A. & Baccarani, M. Chronic myeloid leukaemia. Lancet 370, 342–350 (2007)

    Article  CAS  Google Scholar 

  8. Trumpp, A. & Wiestler, O. D. Mechanisms of disease: cancer stem cells–targeting the evil twin. Nature Clin. Pract. Oncol. 5, 337–347 (2008)

    Article  CAS  Google Scholar 

  9. Borden, E. C. et al. Interferons at age 50: past, current and future impact on biomedicine. Nature Rev. Drug Discov. 6, 975–990 (2007)

    Article  CAS  Google Scholar 

  10. Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998)

    Article  CAS  Google Scholar 

  11. Darnell, J. E., Kerr, I. M. & Stark, G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994)

    Article  ADS  CAS  Google Scholar 

  12. Pichlmair, A. & Reis e Sousa, C. Innate recognition of viruses. Immunity 27, 370–383 (2007)

    Article  CAS  Google Scholar 

  13. Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995)

    Article  ADS  CAS  Google Scholar 

  14. Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996)

    Article  ADS  CAS  Google Scholar 

  15. Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005)

    Article  CAS  Google Scholar 

  16. Adolfsson, J. et al. Upregulation of Flt3 expression within the bone marrow Lin-Sca1+c-kit+ stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15, 659–669 (2001)

    Article  CAS  Google Scholar 

  17. Wilson, A. et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 18, 2747–2763 (2004)

    Article  CAS  Google Scholar 

  18. Wilson, A. et al. Dormant and self-renewing hematopoietic stem cells and their niches. Ann. NY Acad. Sci. 1106, 64–75 (2007)

    Article  ADS  CAS  Google Scholar 

  19. Wilson, A. & Trumpp, A. Bone-marrow haematopoietic-stem-cell niches. Nature Rev. Immunol. 6, 93–106 (2006)

    Article  CAS  Google Scholar 

  20. Yang, X. et al. Prostaglandin A2-mediated stabilization of p21 mRNA through an ERK-dependent pathway requiring the RNA-binding protein HuR. J. Biol. Chem. 279, 49298–49306 (2004)

    Article  CAS  Google Scholar 

  21. van Boxel-Dezaire, A. H., Rani, M. R. & Stark, G. R. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 25, 361–372 (2006)

    Article  CAS  Google Scholar 

  22. Holmes, C. & Stanford, W. L. Concise review: stem cell antigen-1: expression, function, and enigma. Stem Cells 25, 1339–1347 (2007)

    Article  CAS  Google Scholar 

  23. Lerner, C. & Harrison, D. E. 5-Fluorouracil spares hemopoietic stem cells responsible for long-term repopulation. Exp. Hematol. 18, 114–118 (1990)

    CAS  PubMed  Google Scholar 

  24. Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1 . Science 287, 1804–1808 (2000)

    Article  ADS  CAS  Google Scholar 

  25. Orford, K. W. & Scadden, D. T. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nature Rev. Genet. 9, 115–128 (2008)

    Article  CAS  Google Scholar 

  26. O’Hare, T., Corbin, A. S. & Druker, B. J. Targeted CML therapy: controlling drug resistance, seeking cure. Curr. Opin. Genet. Dev. 16, 92–99 (2006)

    Article  Google Scholar 

  27. Atallah, E. & Cortes, J. Optimal initial therapy for patients with newly diagnosed chronic myeloid leukemia in chronic phase. Curr. Opin. Hematol. 14, 138–144 (2007)

    CAS  PubMed  Google Scholar 

  28. Heaney, N. B. & Holyoake, T. L. Therapeutic targets in chronic myeloid leukaemia. Hematol. Oncol. 25, 66–75 (2007)

    Article  CAS  Google Scholar 

  29. Rousselot, P. et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 109, 58–60 (2007)

    Article  CAS  Google Scholar 

  30. Hochhaus, A. First-line management of CML: a state of the art review. J. Natl. Compr. Canc. Netw. 6 (suppl. 2). S1–S10 (2008)

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to M. Aguet for discussions and advice throughout the project, and for providing mouse strains. We thank D. Tough for providing mouse recombinant IFNα4, T. Pedrazzini, W. Stanford and M. Müller for mouse strains, K. Harshman and O. Hagenbüchle and the DAFL team for excellent service and help with the DNA microarrays. We thank C. Dubey and D. Aubry for animal husbandry, genetic screening and technical help, and J. Roberts for FACS sorting. We are grateful to A. Wilson for comments on the manuscript. M.A.G.E. is the recipient of an EMBO long-term fellowship. This work was supported by grants to A.T. from the Swiss National Science Foundation, the Swiss Cancer League, the EU- FP6 Program ‘INTACT’, the EU-FP7 Program ‘EuroSyStem’ and to UK from the Deutsche Forschungsgemeinschaft (SFB432.B15).

Author Contributions A.T., M.A.G.E. and U.K. designed the experiments and analysed the data. M.A.G.E., S.O. and Z.W. performed the experiments. W.E.B.-B. carried out the microarray analysis. A.T., M.A.G.E. and M.D. wrote the paper.

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Authors and Affiliations

  1. Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany,

    Marieke A. G. Essers & Andreas Trumpp

  2. Heidelberg Institute for Stem Cell Technologies and Experimental Medicine (HI-STEM), Im Neuenheimer Feld 280. D-69120 Heidelberg, Germany ,

    Marieke A. G. Essers & Andreas Trumpp

  3. Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC—Swiss Institute for Experimental Cancer Research, School of Life Science, 1015 Lausanne, Switzerland

    Sandra Offner, William E. Blanco-Bose & Andreas Trumpp

  4. Division of Immunology, Paul Ehrlich Institute, D-63225 Langen, Germany

    Zoe Waibler & Ulrich Kalinke

  5. TWINCORE—Centre for Experimental and Clinical Infection Research Feodor-Lynen-Str. 7, 30625 Hannover, Germany

    Ulrich Kalinke

  6. Service and Central Laboratory of Hematology, CHUV, University Hospitals of Lausanne, CH-1011 Lausanne, Switzerland

    Michel A. Duchosal

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  1. Marieke A. G. Essers
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Correspondence to Andreas Trumpp.

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Essers, M., Offner, S., Blanco-Bose, W. et al. IFNα activates dormant haematopoietic stem cells in vivo. Nature 458, 904–908 (2009). https://doi.org/10.1038/nature07815

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