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

Amelie Guitart, Theoni Panagopoulou, Arnaud Villacreces, Milica Vukovic, Catarina Sepulveda, Lewis Allen, Roderick N. Carter, Louie van de Lagemaat, Marcos Morgan, Peter Giles, Zuzanna Sas, Marta Vila Gonzalez, Hannah Lawson, Jasmin Paris, Joy Edward-Hicks, Katrin Schaak, Chithra Subramani, Deniz Gezer, Alejandro Armesilla-Diaz, Jimi Bukowski-WillsAaron Easterbrook, David Coman, Chi Wai Eric So, Donal O'Carroll, Douglas Vernimmen, Neil P Rodrigues, Patrick J Pollard, Nicholas M. Morton, Andrew Finch, Kamil R. Kranc

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)719-735
JournalJournal of Experimental Medicine
Volume214
Issue number3
DOIs
Publication statusPublished - 15 Feb 2017

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