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Awakening dormant haematopoietic stem cells

Nature Reviews Immunology volume 10, pages 201–209 (2010)Cite this article

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Abstract

Haematopoietic stem cells (HSCs) in mouse bone marrow are located in specialized niches as single cells. During homeostasis, signals from this environment keep some HSCs dormant, which preserves long-term self-renewal potential, while other HSCs actively self renew to maintain haematopoiesis. In response to haematopoietic stress, dormant HSCs become activated and rapidly replenish the haematopoietic system. Interestingly, three factors — granulocyte colony-stimulating factor, interferon-α and arsenic trioxide — have been shown to efficiently activate dormant stem cells and thereby could break their resistance to anti-proliferative chemotherapeutics. Thus, we propose that two-step strategies could target resistant leukaemic stem cells by priming tumours with activators of dormancy followed by chemotherapy or targeted therapies.

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Figure 1: A model of dormant and homeostatic haematopoietic stem cells and their dynamic behaviour in response to haematopoietic injury.
Figure 2: Interferon-α promotes cell cycle entry of dormant and homeostatic haematopoietic stem cells.
Figure 3: Leukaemic stem cells may be targeted by a two-step strategy.

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Acknowledgements

This work was supported in part by grants awarded to A.T. from the European Union 7th Framework Programme 'EuroSyStem' and the BioRN Spitzencluster 'Molecular and Cell Based Medicine' funded by the German 'Bundesministerium für Bildung und Forschung' (BMBF).

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Authors and Affiliations

  1. and the Division of Stem Cells and Cancer, Andreas Trumpp and Marieke Essers are at the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69,120 Heidelberg, Germany.,

    Andreas Trumpp & Marieke Essers

  2. Anne Wilson is at the Ludwig Institute for Cancer Research Ltd., Lausanne Branch, University of Lausanne, 1066 Epalinges, Switzerland.,

    Anne Wilson

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Correspondence to Andreas Trumpp.

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Glossary

5-Fluorouracil

(5-FU). A pyrimidine analogue, which is used as a drug in the treatment of cancer. It belongs to the familiy of drugs called anti-metabolites and mainly functions as a thymidylate synthase inhibitor. One of its main side effects is myelosuppression, shown by a massive loss of bone marrow and peripheral haematopoietic cells in 5-FU treated mice. This induces a feedback loop that activates previously dormant and therefore resistant HSCs to proliferate and self renew.

Bromodeoxyuridine

(BrdU). A thymidine analogue that is incorporated into DNA during DNA replication. In vivo or in vitro treatment with BrdU can allow the detection of dividing cells by intracellular staining with fluorescence-labelled BrdU-specific antibodies followed by flow cytometry.

Chronic myeloid leukaemia

(CML). A cancer of the white blood cells. This form of leukaemia is a clonal bone marrow stem cell disorder, which is characterized by the proliferation of mature granulocytes and their precursors in the bone marrow, followed by accumulation of these cells in the blood. CML is associated with a characteristic chromosomal translocation, the Philadelphia chromosome, generating an aberrant constitutively active tyrosine kinase called BCR–ABL. Treatment with the tyrosine kinase inhibitor imatinib mesylate has dramatically improved the survival of patients with CML over the past decade.

Competitive-repopulation assay

A functional assay for measuring the activity of mouse HSCs. The HSC content of an undefined population of cells is determined by mixing the cells with a defined number of fresh bone marrow cells from another source. After transplantation into lethally irradiated mice, genetic markers are used to distinguish progeny from the two HSC sources in blood and haematopoietic organs. These measurements allow the assessment of HSC activity.

Imatinib mesylate

(Gleevec/Glivec; Novartis). A tyrosine kinase inhibitor used to treat CML, gastrointestinal stromal tumours and other cancers caused by constitutively active tyrosine kinases, including BCR–ABL and KIT. In CML, imatinib mesylate binds to the site of tyrosine kinase activity of the fusion protein BCR–ABL and therefore prevents its activity.

Mx1–Cre allele

An allele expressed in Mx1–Cre transgenic mice, in which the type I IFN-inducible Mx1 promoter controls expression of the Cre recombinase. By injection of polyinosinic–polycytidylic acid (polyI:C), type I IFNs are produced, which induces Cre recombinase expression. This induces highly efficient excision of loxP-flanked genes in HSCs and other blood cells, as well as hepatocytes.

Side population

The ability of a cell to efflux the Hoechst 33342 dye by a multi-drug resistant-like transporter expressed on the cell surface. This can be measured by flow cytometry and used to enrich for murine HSCs.

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Trumpp, A., Essers, M. & Wilson, A. Awakening dormant haematopoietic stem cells. Nat Rev Immunol 10, 201–209 (2010). https://doi.org/10.1038/nri2726

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