Cited by 90Hematopoietic Stem Cell TransplantationCancer, Hypoxia, and MetabolismAcute Myeloid Leukemia Research

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

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Guitart, Amelie V., Panagopoulou, Theano I., Villacreces, Arnaud, Vukovic, Milica, Sepulveda, Catarina, Allen, Lewis, Carter, Roderick N., van de Lagemaat, Louie N. +22 more·2017·Journal of Experimental Medicine

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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Authors
Guitart, A. V., Panagopoulou, T. I., Villacreces, A., Vukovic, M., Sepulveda, C., Allen, L., Carter, R. N., van de Lagemaat, L. N., Morgan, M., Giles, P., Sas, Z., Gonzalez, M. V., Lawson, H., Paris, J., Edwards-Hicks, J., Schaak, K., Subramani, C., Gezer, D., Armesilla-Diaz, A., Wills, J., Easterbrook, A., Coman, D., So, C. W. E., O’Carroll, D., Vernimmen, D., Rodrigues, N. P., Pollard, P. J., Morton, N. M., Finch, A., & Kranc, K. R.
Affiliations
  • MRC Centre for Regenerative Medicine (GB)
  • Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK 1
  • The Queen's Medical Research Institute (GB)
  • Wales Gene Park (GB)
  • Edinburgh Cancer Research (GB)
  • Mater Private Hospital (AU)
  • Children's Health Queensland Hospital and Health Service (AU)
  • King's College London (GB)
  • Roslin Institute (GB)
  • Cardiff University (GB)
Corresponding author
Kranc, Kamil R.
Venue
Journal of Experimental Medicine
Published
2017-02-15
Volume
214
Issue
3
Pages
719-735
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
OpenAlex
W2588146519
Cited by
86
References
71
Citations by year
2026: 9 · 2025: 3 · 2024: 10 · 2023: 13 · 2022: 10 · 2021: 15 · 2020: 9 · 2019: 8 · 2018: 3 · 2017: 6
FWCI
5.48
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion, cc-by)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
  • Griffith Research Online (submittedVersion, cc-by)
Funders
  • Kay Kendall Leukaemia Fund
  • Cancer Research UK
  • Bloodwise
  • Wellcome Trust
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
fumarate hydratase, hematopoietic stem cells, fumarate accumulation, TCA cycle, mitochondrial respiration, hematopoiesis, leukemia-initiating cells, lymphoid differentiation, stem cell self-renewal
MeSH terms
Animals, Female, Fumarate Hydratase, Fumarates, Hematopoiesis, Hematopoietic Stem Cells, Histones, Mice, Inbred C57BL, Mitochondria, Oxygen Consumption, Leukemia, Myeloid, Acute, NF-E2-Related Factor 2, Mice

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