Afficher la couverture 'Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions | Guitart, Amelie, V' en grand format
/5

0 avis

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

Archive ouverte

Guitart, Amelie, V | Panagopoulou, Theano | Villacreces, Arnaud | Vukovic, Milica | Sepulveda, Catarina | Allen, Lewis | Carter, Roderick | van de Lagemaat, Louie | 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 | Easterbrook, Aaron | Coman, David | So, Chi Wai Eric | O'Carroll, Donal | Vernimmen, Douglas | Rodrigues, Neil | Pollard, Patrick | Morton, Nicholas | Finch, Andrew | Kranc, Kamil | O’carroll, Donal

Edité par CCSD ; Rockefeller University Press -

International audience. 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.

Consulter en ligne

Suggestions

Du même auteur

Adult hematopoietic stem cells lacking Hif-1α self-renew normally

Archive ouverte | Vukovic, Milica | CCSD

International audience. The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-induci...

Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

Archive ouverte | Vukovic, Milica | CCSD

International audience. Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α)...

JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells

Archive ouverte | Lawson, Hannah | CCSD

International audience. Abstract Lifelong multilineage hematopoiesis critically depends on rare hematopoietic stem cells (HSCs) that reside in the hypoxic bone marrow microenvironment. Although the role of the canon...

Chargement des enrichissements...