Methionine aminopeptidase 2 is required for HSC initiation and proliferation
Methionine aminopeptidase 2 is required for HSC initiation and proliferation
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DOI：
10.1182/blood-2011-04-350173
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发表时间：
2011-11-17
期刊：
影响因子：
20.3
通讯作者：
Leung, Anskar Y. H.
中科院分区：
文献类型：
--
作者：
Ma, Alvin C. H.;Fung, Tsz K.;Leung, Anskar Y. H.
在化学筛选中，我们测试了富马青霉素衍生物的抗血管生成作用，并确定富马青霉素是斑马鱼胚胎最终造血的抑制剂。已知富马青霉素靶向蛋氨酸氨基肽酶II (MetAP2)，这种酶在造血中的功能尚不清楚。我们利用斑马鱼胚胎和人脐带血模型研究了MetAP2在造血中的作用。斑马鱼metap2在胚胎发育早期和后期在躯体区、尾端造血组织和肾原管中普遍表达。morolino和fumagillin抑制了Metap2，导致mpo在受精后18小时表达增加，而c-myb在受精后36小时沿背主动脉腹壁上表达减少。它还破坏了Tg-(fli1:gfp)胚胎的节段间血管，但不影响主要轴向血管的发育。富马青霉素抑制CB CD34（+）细胞中的MetAP2对总体克隆生成活性没有影响，但显著降低了它们在免疫缺陷非肥胖糖尿病/严重联合免疫缺陷小鼠中的植入。斑马鱼中metap2的敲除和富马青霉素对斑马鱼和人CB CD34（+）细胞的抑制抑制了钙调蛋白激酶II的活性并诱导ERK磷酸化。这项研究证明了MetAP2在决定性造血中的作用，以及与非规范Wnt和ERK信号的可能联系。(血。2011;118 (20):5448 - 5457)
In a chemical screening, we tested the antiangiogenic effects of fumagillin derivatives and identified fumagillin as an inhibitor of definitive hematopoiesis in zebrafish embryos. Fumagillin is known to target methionine aminopeptidase II (MetAP2), an enzyme whose function in hematopoiesis is unknown. We investigated the role of MetAP2 in hematopoiesis by using zebrafish embryo and human umbilical cord blood models. Zebrafish metap2 was expressed ubiquitously during early embryogenesis and later in the somitic region, the caudal hematopoietic tissue, and pronephric duct. metap2 was inhibited by morpholino and fumagillin treatment, resulting in increased mpo expression at 18 hours postfertilization and reduced c-myb expression along the ventral wall of dorsal aorta at 36 hours postfertilization. It also disrupted intersegmental vessels in Tg-(fli1:gfp) embryos without affecting development of major axial vasculatures. Inhibition of MetAP2 in CB CD34(+) cells by fumagillin had no effect on overall clonogenic activity but significantly reduced their engraftment into immunodeficient nonobese diabetes/severe combined immunodeficiency mice. metap2 knockdown in zebrafish and inhibition by fumagillin in zebrafish and human CB CD34(+) cells inhibited Calmodulin Kinase II activity and induced ERK phosphorylation. This study demonstrated a hithertoun-described role of MetAP2 in definitive hematopoiesis and a possible link to noncanonical Wnt and ERK signaling. (Blood. 2011;118(20):5448-5457)