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dc.contributor.authorGuitart, Amelie V
dc.contributor.authorPanagopoulou, Theano I
dc.contributor.authorVillacreces, Arnaud
dc.contributor.authorVukovic, Milica
dc.contributor.authorSepulveda, Catarina
dc.contributor.authorAllen, Lewis
dc.contributor.authorCarter, Roderick N
dc.contributor.authorvan de Lagemaat, Louie N
dc.contributor.authorMorgan, Marcos
dc.contributor.authorGiles, Peter
dc.contributor.authorSas, Zuzanna
dc.contributor.authorGonzalez, Marta Vila
dc.contributor.authorLawson, Hannah
dc.contributor.authorComan, David
dc.contributor.authoret al.
dc.date.accessioned2022-10-31T01:35:56Z
dc.date.available2022-10-31T01:35:56Z
dc.date.issued2017
dc.identifier.issn0022-1007en_US
dc.identifier.doi10.1084/jem.20161087en_US
dc.identifier.urihttp://hdl.handle.net/10072/405930
dc.description.abstractStrict 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.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.publisherROCKEFELLER UNIV PRESSen_US
dc.relation.ispartofpagefrom719en_US
dc.relation.ispartofpageto735en_US
dc.relation.ispartofissue3en_US
dc.relation.ispartofjournalThe Journal of Experimental Medicineen_US
dc.relation.ispartofvolume214en_US
dc.subject.fieldofresearchBiomedical and clinical sciencesen_US
dc.subject.fieldofresearchcode32en_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsLife Sciences & Biomedicineen_US
dc.subject.keywordsImmunologyen_US
dc.subject.keywordsMedicine, Research & Experimentalen_US
dc.subject.keywordsResearch & Experimental Medicineen_US
dc.titleFumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functionsen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationGuitart, AV; Panagopoulou, TI; Villacreces, A; Vukovic, M; Sepulveda, C; Allen, L; Carter, RN; van de Lagemaat, LN; Morgan, M; Giles, P; Sas, Z; Gonzalez, MV; Lawson, H; Coman, D; et al, Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions, The Journal of Experimental Medicine, 2017, 214 (3), pp. 719-735en_US
dcterms.dateAccepted2017-01-20
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2021-07-14T00:09:23Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© 2017 Guitart et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).en_US
gro.hasfulltextFull Text
gro.griffith.authorComan, Dave J.


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