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The Lkb1 metabolic sensor maintains haematopoietic stem cell survival

Nature volume 468, pages 659–663 (2010)Cite this article

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An Erratum to this article was published on 06 July 2011

This article has been updated

Abstract

Haematopoietic stem cells (HSCs) can convert between growth states that have marked differences in bioenergetic needs. Although often quiescent in adults, these cells become proliferative upon physiological demand. Balancing HSC energetics in response to nutrient availability and growth state is poorly understood, yet essential for the dynamism of the haematopoietic system. Here we show that the Lkb1 tumour suppressor is critical for the maintenance of energy homeostasis in haematopoietic cells. Lkb1 inactivation in adult mice causes loss of HSC quiescence followed by rapid depletion of all haematopoietic subpopulations. Lkb1-deficient bone marrow cells exhibit mitochondrial defects, alterations in lipid and nucleotide metabolism, and depletion of cellular ATP. The haematopoietic effects are largely independent of Lkb1 regulation of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling. Instead, these data define a central role for Lkb1 in restricting HSC entry into cell cycle and in broadly maintaining energy homeostasis in haematopoietic cells through a novel metabolic checkpoint.

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Figure 1: Lkb1 is required for haematopoiesis.
Figure 2: Cell-autonomous role of Lkb1 in haematopoiesis.
Figure 3: Impact of Lkb1 inactivation on proliferation and apoptosis.
Figure 4: mTORC1 inhibition and AMPK activation do not rescue bone marrow failure in Lkb1 mutants.
Figure 5: Inactivation of Lkb1 alters mitochondrial function of bone marrow cells.

Change history

  • 06 July 2011

    Figs 1 and 2 have been corrected in the original online HTML and PDF versions as described in the accompanying Erratum.

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Acknowledgements

We would like to thank the Harvard Stem Cell Institute Flow Cytometry Core and D. Brown and the MGH Electron Microscope Imaging Core for expertise and advice. V. Levy and M. Leisa provided technical assistance in the SeaHorse measurements. D. Van Buren provided advice and assistance in pilot experiments. We thank A. Camacho for mouse colony assistance. We would also like to thank A. Kimmelman, R. Mostoslavsky, M. Vander Heiden, L. Ellisen, W. Kim and M. Ivan for discussions and critical review of the manuscript. We are grateful to S. Morrison and R. DePinho for sharing unpublished data. N.B. would like to acknowledge support from NIH U01 CA141576-01. D.T.S would like to acknowledge support from NIH DK050234 and Ellison Medical Foundation. S.G. was supported by a Massachusetts Biotechnology Research Council Tosteson Fellowship. S.Z.X. was supported by an NIH Ruth L. Kirschstein National Research Service Award.

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Author notes

  1. Sushma Gurumurthy and Stephanie Z. Xie: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, Massachusetts, USA

    Sushma Gurumurthy, Stephanie Z. Xie, Brinda Alagesan, Judith Kim, Rushdia Z. Yusuf, Borja Saez, Alexandros Tzatsos, David T. Scadden & Nabeel Bardeesy

  2. Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Boston, 02115, Massachusetts, USA

    Stephanie Z. Xie, Rushdia Z. Yusuf, Borja Saez & David T. Scadden

  3. Helicos BioSciences Corporation, Cambridge, 02139, Massachusetts, USA

    Fatih Ozsolak & Patrice Milos

  4. Center for Biomedical Informatics and Informatics Program, Children’s Hospital, and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Francesco Ferrari & Peter J. Park

  5. Department of Medicine, Evans Research Center, Mitochondria ARC, Boston University Medical Center, Boston, 02118, Massachusetts, USA

    Orian S. Shirihai

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  1. Sushma Gurumurthy
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Contributions

S.G. and S.Z.X. performed the experiments with assistance from B.A., J.K., A.T., B.S. and R.Z.Y. S.G., S.Z.X., D.T.S. and N.B. designed the experiments, analysed and evaluated all data, and wrote the manuscript. F.O. and P.M. performed the RNA sequencing. F.F. and P.J.P. analysed the RNA sequencing data. O.S.S. designed and evaluated the oxygen consumption experiments.

Corresponding authors

Correspondence to David T. Scadden or Nabeel Bardeesy.

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The authors declare no competing financial interests.

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Gurumurthy, S., Xie, S., Alagesan, B. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010). https://doi.org/10.1038/nature09572

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