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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.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.
dc.relation.ispartofjournalThe Journal of Experimental Medicine
dc.subject.fieldofresearchBiomedical and clinical sciences
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsMedicine, Research & Experimental
dc.subject.keywordsResearch & Experimental Medicine
dc.titleFumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions
dc.typeJournal article
dc.type.descriptionC1 - Articles
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. 719-735
gro.hasfulltextNo Full Text
gro.griffith.authorComan, Dave J.

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