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Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions

Guitart, AV; Panagopoulou, TI; Villacreces, A; Vukovic, M; Sepulveda, C; Allen, L; Carter, RN; ... Kranc, KR; + view all (2017) Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions. Journal of Experimental Medicine , 214 (3) pp. 719-735. 10.1084/jem.20161087. Green open access

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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.

Type: Article
Title: Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions
Open access status: An open access version is available from UCL Discovery
DOI: 10.1084/jem.20161087
Publisher version: http://dx.doi.org/10.1084/jem.20161087
Language: English
Additional information: © 2017 Guitart et al. https://creativecommons.org/licenses/by/4.0/ This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Immunology, Medicine, Research & Experimental, Research & Experimental Medicine, ACUTE MYELOID-LEUKEMIA, MITOCHONDRIAL RESPIRATORY CAPACITY, SINGLE TRANSLATION PRODUCT, GERMLINE MUTATIONS, TUMOR-SUPPRESSOR, HYPOXIC NICHE, INHIBITION, GENE, HIF-1-ALPHA, HISTONE
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
URI: https://discovery.ucl.ac.uk/id/eprint/10053182
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