Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 3, Pages 719-735Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20161087
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Funding
- Kay Kendall Leukaemia Fund
- Cancer Research UK
- Bloodwise
- Tenovus Scotland
- Wellcome Trust's Institutional Strategic Support Fund
- BBSRC [BBS/E/D/10002071, BBS/E/D/20221657] Funding Source: UKRI
- MRC [MR/L012766/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/D/20221657] Funding Source: researchfish
- Cancer Research UK [16753, 14633] Funding Source: researchfish
- Medical Research Council [MR/P010008/1, 1360014, MR/L012766/1] Funding Source: researchfish
- Wellcome Trust [100981/Z/13/Z] Funding Source: researchfish
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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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