The Lkb1 metabolic sensor maintains haematopoietic stem cell survival

Sushma Gurumurthy, Stephanie Z. Xie, Brinda Alagesan, Judith Kim, Rushdia Z. Yusuf, Borja Saez, Alexandros Tzatsos, Fatih Ozsolak, Patrice Milos, Francesco Ferrari, Peter J. Park, Orian S. Shirihai, David T. Scadden () and Nabeel Bardeesy ()
Additional contact information
Sushma Gurumurthy: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School
Stephanie Z. Xie: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School
Brinda Alagesan: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School
Judith Kim: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School
Rushdia Z. Yusuf: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School
Borja Saez: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School
Alexandros Tzatsos: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School
Fatih Ozsolak: Helicos BioSciences Corporation
Patrice Milos: Helicos BioSciences Corporation
Francesco Ferrari: Center for Biomedical Informatics and Informatics Program, Children’s Hospital, and Harvard Medical School
Peter J. Park: Center for Biomedical Informatics and Informatics Program, Children’s Hospital, and Harvard Medical School
Orian S. Shirihai: Evans Research Center, Mitochondria ARC, Boston University Medical Center
David T. Scadden: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School
Nabeel Bardeesy: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School

Nature, 2010, vol. 468, issue 7324, 659-663

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature09572

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