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Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.
Guitart, Amelie V; Panagopoulou, Theano I; Villacreces, Arnaud; Vukovic, Milica; Sepulveda, Catarina; Allen, Lewis; Carter, Roderick N; van de Lagemaat, Louie N; Morgan, Marcos; Giles, Peter; Sas, Zuzanna; Gonzalez, Marta Vila; Lawson, Hannah; Paris, Jasmin; Edwards-Hicks, Joy; Schaak, Katrin; Subramani, Chithra; Gezer, Deniz; Armesilla-Diaz, Alejandro; Wills, Jimi; Easterbrook, Aaron; Coman, David; So, Chi Wai Eric; O'Carroll, Donal; Vernimmen, Douglas; Rodrigues, Neil P; Pollard, Patrick J; Morton, Nicholas M; Finch, Andrew; Kranc, Kamil R.
Afiliación
  • Guitart AV; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Panagopoulou TI; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Villacreces A; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Vukovic M; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Sepulveda C; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Allen L; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Carter RN; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • van de Lagemaat LN; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Morgan M; The Roslin Institute, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Giles P; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Sas Z; Wales Gene Park and Wales Cancer Research Centre, Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF10 3XQ, Wales, UK.
  • Gonzalez MV; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Lawson H; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Paris J; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Edwards-Hicks J; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Schaak K; Edinburgh Cancer Research UK Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Subramani C; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Gezer D; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Armesilla-Diaz A; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Wills J; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Easterbrook A; Edinburgh Cancer Research UK Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Coman D; Mater Children's Private Hospital Brisbane, South Brisbane, Queensland 4101, Australia.
  • So CW; Department of Metabolic Medicine, The Lady Cilento Children's Hospital, South Brisbane, Queensland 4101, Australia.
  • O'Carroll D; Department of Haematological Medicine, Division of Cancer Studies, King's College London, London WC2R 2LS, England, UK.
  • Vernimmen D; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Rodrigues NP; The Roslin Institute, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Pollard PJ; The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff CF10 3XQ, Wales, UK.
  • Morton NM; Edinburgh Cancer Research UK Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Finch A; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
  • Kranc KR; Edinburgh Cancer Research UK Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
J Exp Med ; 214(3): 719-735, 2017 03 06.
Article en En | MEDLINE | ID: mdl-28202494
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-specific Fh1 deletion (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 propagated Meis1/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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Fumarato Hidratasa Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: J Exp Med Año: 2017 Tipo del documento: Article País de afiliación: Reino Unido
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Fumarato Hidratasa Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: J Exp Med Año: 2017 Tipo del documento: Article País de afiliación: Reino Unido