Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.
Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.
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DOI：
10.1084/jem.20161087
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发表时间：
2017-03-06
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影响因子：
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通讯作者：
Kranc KR
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作者：
Guitart AV;Panagopoulou TI;Villacreces A;Vukovic M;Sepulveda C;Allen L;Carter RN;van de Lagemaat LN;Morgan M;Giles P;Sas Z;Gonzalez MV;Lawson H;Paris J;Edwards-Hicks J;Schaak K;Subramani C;Gezer D;Armesilla-Diaz A;Wills J;Easterbrook A;Coman D;So CW;O'Carroll D;Vernimmen D;Rodrigues NP;Pollard PJ;Morton NM;Finch A;Kranc KR
Guitart等人对造血系统中的克雷布斯循环酶延胡索酸水合酶（Fh 1）进行了体内遗传解剖。他们的研究揭示了Fh 1在调节造血干细胞生物学和白血病转化中的多方面功能。严格调节干细胞代谢对于组织功能和肿瘤抑制是必不可少的。在这项研究中，我们研究了延胡索酸水合酶（Fh 1），线粒体三羧酸（TCA）循环和胞浆延胡索酸代谢的关键组成部分，在正常和白血病造血的作用。造血特异性Fh 1缺失（导致内源性富马酸盐蓄积和遗传性TCA循环阻滞，反映为最大线粒体呼吸降低）导致致死性胎肝造血缺陷和造血干细胞（HSC）衰竭。线粒体外Fh 1的再表达（使富马酸水平正常化，但不是最大线粒体呼吸）挽救了这些表型，表明细胞富马酸积累的因果作用。然而，缺乏线粒体Fh 1的HSC（富马酸水平正常，但最大线粒体呼吸功能缺陷）无法自我更新，并显示淋巴样分化缺陷。相反，缺乏线粒体Fh 1的白血病起始细胞有效地繁殖Meis 1/Hoxa 9驱动的白血病。因此，我们确定了富马酸代谢在HSC维持和造血分化中的新作用，并揭示了正常造血和白血病增殖中对线粒体Fh 1的不同需求。
Guitart et al. performed an in vivo genetic dissection of the Krebs cycle enzyme fumarate hydratase (Fh1) in the hematopoietic system. Their investigations revealed multifaceted functions of Fh1 in the regulation of hematopoietic stem cell biology and leukemic transformation. 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.