Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions-Reference-Cited by-同舟云学术

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

Published:2017-02-15 Issue:3 Volume:214 Page:719-735
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Guitart Amelie V.¹^ORCID,Panagopoulou Theano I.¹^ORCID,Villacreces Arnaud¹^ORCID,Vukovic Milica¹,Sepulveda Catarina¹^ORCID,Allen Lewis¹^ORCID,Carter Roderick N.²^ORCID,van de Lagemaat Louie N.¹³,Morgan Marcos¹,Giles Peter⁴^ORCID,Sas Zuzanna¹^ORCID,Gonzalez Marta Vila¹,Lawson Hannah¹^ORCID,Paris Jasmin¹,Edwards-Hicks Joy⁵^ORCID,Schaak Katrin¹^ORCID,Subramani Chithra¹^ORCID,Gezer Deniz¹,Armesilla-Diaz Alejandro¹^ORCID,Wills Jimi⁵,Easterbrook Aaron⁶^ORCID,Coman David⁷,So Chi Wai Eric⁸,O’Carroll Donal¹,Vernimmen Douglas³,Rodrigues Neil P.⁹,Pollard Patrick J.⁵,Morton Nicholas M.²,Finch Andrew⁵^ORCID,Kranc Kamil R.¹⁵^ORCID

Affiliation:

1. Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK

2. Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK

3. The Roslin Institute, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK

4. Wales Gene Park and Wales Cancer Research Centre, Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF10 3XQ, Wales, UK

5. Edinburgh Cancer Research UK Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK

6. Mater Children’s Private Hospital Brisbane, South Brisbane, Queensland 4101, Australia

7. Department of Metabolic Medicine, The Lady Cilento Children’s Hospital, South Brisbane, Queensland 4101, Australia

8. Department of Haematological Medicine, Division of Cancer Studies, King’s College London, London WC2R 2LS, England, UK

9. The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff CF10 3XQ, Wales, UK

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.

Funder

Kay Kendall Leukaemia Fund

Cancer Research UK

Bloodwise

Wellcome Trust

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Link

http://rupress.org/jem/article-pdf/214/3/719/1166278/jem_20161087.pdf

Reference69 articles.