The Lkb1 metabolic sensor maintains haematopoietic stem cell survival.
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.
Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Sushma
S
Gurumurthy
Stephanie Z
SZ
Xie
Brinda
B
Alagesan
Judith
J
Kim
Rushdia Z
RZ
Yusuf
Borja
B
Saez
Alexandros
A
Tzatsos
Fatih
F
Ozsolak
Patrice
P
Milos
Francesco
F
Ferrari
Peter J
PJ
Park
Orian S
OS
Shirihai
David T
DT
Scadden
Nabeel
N
Bardeesy
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D004734:Energy Metabolism; D004789:Enzyme Activation; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D050356:Lipid Metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D046912:Multiprotein Complexes; D011506:Proteins; D025521:Tumor Suppressor Proteins; D000255:Adenosine Triphosphate; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases