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Fumarate hydratase is a critical regulator of hematopoietic stem cell functions

Guitart, Amelie V, Panagopoulou, Theano I, Villacreces, Arnaud, Vukovic, Milica, Sepulveda, Catarina, Allen, Lewis, Carter, Roderick N, Lagemaat, Louie N van de, Morgan, Marcos, Giles, Peter, Sas, Zuzanna, Gonzalez, Marta Vila, Lawson, Hannah, Paris, Jasmin, Edwards-Hicks, Joy, Schaak, Katrin, Subramani, Chithra, Gezer, Deniz, Armesilla-Diaz, Alejandro, Wills, Jimi Carlo, Easterbrook, Aaron, Coman, David, Wai, Chi, So, Eric, O'Carroll, Donal, Vernimmen, Douglas, Rodrigues, Neil, Pollard, Patrick J, Morton, Nicholas M, Finch, Andrew and Kranc, Kamil R 2017. Fumarate hydratase is a critical regulator of hematopoietic stem cell functions. Journal of Experimental Medicine 214 (3) , 719. 10.1084/jem.20161087

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: Rockefeller University Press
ISSN: 0022-1007
Date of First Compliant Deposit: 17 January 2017
Date of Acceptance: 20 January 2017
Last Modified: 11 Oct 2017 10:51
URI: http://orca.cf.ac.uk/id/eprint/97489

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