Fumarate Hydratase is a Critical Metabolic Regulator of Hematopoietic Stem Cell Functions

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2017 Feb 17

PMID 28202494

Citations 49

Authors

Amelie V Guitart

Theano I Panagopoulou

Arnaud Villacreces

Milica Vukovic

Catarina Sepulveda

Lewis Allen

Roderick N Carter

Louie N van de Lagemaat

Marcos Morgan

Peter Giles

Zuzanna Sas

Marta Vila Gonzalez

Hannah Lawson

Jasmin Paris

Joy Edwards-Hicks

Katrin Schaak

Chithra Subramani

Deniz Gezer

Alejandro Armesilla-Diaz

Jimi Wills

Aaron Easterbrook

David Coman

Chi Wai Eric So

Donal OCarroll

Douglas Vernimmen

Neil P Rodrigues

Patrick J Pollard

Nicholas M Morton

Andrew Finch

Kamil R Kranc

Affiliations

Soon will be listed here.

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 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 /-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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