title: Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.
abstract: Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specificFh1deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure. Reexpression of extramitochondrial Fh1 (which normalized fumarate levels but not maximal mitochondrial respiration) rescued these phenotypes, indicating the causal role of cellular fumarate accumulation. However, HSCs lacking mitochondrial Fh1 (which had normal fumarate levels but defective maximal mitochondrial respiration) failed to self-renew and displayed lymphoid differentiation defects. In contrast, leukemia-initiating cells lacking mitochondrial Fh1 efficiently propagatedMeis1/Hoxa9-driven leukemia. Thus, we identify novel roles for fumarate metabolism in HSC maintenance and hematopoietic differentiation and reveal a differential requirement for mitochondrial Fh1 in normal hematopoiesis and leukemia propagation.
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Amelie V
authors.identifier: 0000-0002-2336-7716
authors.initials: AV
authors.lastname: Guitart
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Theano I
authors.identifier: 0000-0003-2947-216X
authors.initials: TI
authors.lastname: Panagopoulou
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Arnaud
authors.identifier: 0000-0002-2868-2264
authors.initials: A
authors.lastname: Villacreces
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Milica
authors.initials: M
authors.lastname: Vukovic
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Catarina
authors.identifier: 0000-0002-1307-8101
authors.initials: C
authors.lastname: Sepulveda
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Lewis
authors.identifier: 0000-0003-4975-9563
authors.initials: L
authors.lastname: Allen
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Roderick N
authors.identifier: 0000-0001-6565-9939
authors.initials: RN
authors.lastname: Carter
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.|The Roslin Institute, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Louie N
authors.initials: LN
authors.lastname: van de Lagemaat
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Marcos
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Wales Gene Park and Wales Cancer Research Centre, Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF10 3XQ, Wales, UK.
authors.forename: Peter
authors.identifier: 0000-0003-3143-6854
authors.initials: P
authors.lastname: Giles
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Zuzanna
authors.identifier: 0000-0001-7815-7938
authors.initials: Z
authors.lastname: Sas
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Marta Vila
authors.initials: MV
authors.lastname: Gonzalez
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Hannah
authors.identifier: 0000-0003-1450-1343
authors.initials: H
authors.lastname: Lawson
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Paris
authors.affiliation: Edinburgh Cancer Research UK Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Joy
authors.identifier: 0000-0001-7557-3960
authors.initials: J
authors.lastname: Edwards-Hicks
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Katrin
authors.identifier: 0000-0001-6395-4184
authors.initials: K
authors.lastname: Schaak
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Chithra
authors.identifier: 0000-0002-0735-0172
authors.initials: C
authors.lastname: Subramani
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Deniz
authors.initials: D
authors.lastname: Gezer
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Alejandro
authors.identifier: 0000-0002-3874-4115
authors.initials: A
authors.lastname: Armesilla-Diaz
authors.affiliation: Edinburgh Cancer Research UK Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Jimi
authors.initials: J
authors.lastname: Wills
authors.affiliation: Mater Children's Private Hospital Brisbane, South Brisbane, Queensland 4101, Australia.
authors.forename: Aaron
authors.identifier: 0000-0002-6883-6846
authors.initials: A
authors.lastname: Easterbrook
authors.affiliation: Department of Metabolic Medicine, The Lady Cilento Children's Hospital, South Brisbane, Queensland 4101, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Coman
authors.affiliation: Department of Haematological Medicine, Division of Cancer Studies, King's College London, London WC2R 2LS, England, UK.
authors.forename: Chi Wai Eric
authors.initials: CW
authors.lastname: So
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Donal
authors.initials: D
authors.lastname: O'Carroll
authors.affiliation: The Roslin Institute, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Douglas
authors.initials: D
authors.lastname: Vernimmen
authors.affiliation: The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff CF10 3XQ, Wales, UK.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Rodrigues
authors.affiliation: Edinburgh Cancer Research UK Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pollard
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Morton
authors.affiliation: Edinburgh Cancer Research UK Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Andrew
authors.identifier: 0000-0002-8065-4623
authors.initials: A
authors.lastname: Finch
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK kamil.kranc@ed.ac.uk.|Edinburgh Cancer Research UK Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Kamil R
authors.identifier: 0000-0001-7547-4989
authors.initials: KR
authors.lastname: Kranc
mesh_terms: D000818:Animals; D005260:Female; D005649:Fumarate Hydratase / Q000502:physiology*; D005650:Fumarates / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D010101:Oxygen Consumption
chemical_list: D005650:Fumarates; D006657:Histones; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D005649:Fumarate Hydratase