title: Methionine aminopeptidase 2 is required for HSC initiation and proliferation.
abstract: 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 knock-down 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 hitherto-undescribed role of MetAP2 in definitive hematopoiesis and a possible link to noncanonical Wnt and ERK signaling.
authors.affiliation: Department of Medicine, LKS Faculty of Medicine, Queen Mary Hospital, Pok Fu Lam Road, Hong Kong.
authors.forename: Alvin C H
authors.initials: AC
authors.lastname: Ma
authors.forename: Tsz K
authors.initials: TK
authors.lastname: Fung
authors.forename: Rachel H C
authors.initials: RH
authors.lastname: Lin
authors.forename: Martin I S
authors.initials: MI
authors.lastname: Chung
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Ekker
authors.forename: Anskar Y H
authors.initials: AY
authors.lastname: Leung
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D002455:Cell Division / Q000502:physiology; D003510:Cyclohexanes / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005312:Fetal Blood / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008666:Metalloendopeptidases / Q000235:genetics / Q000502:physiology*; D063208:Methionyl Aminopeptidases; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D038042:Myelopoiesis / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D006023:Glycoproteins; D012717:Sesquiterpenes; D051153:Wnt Proteins; C026211:fumagillin; D048049:Extracellular Signal-Regulated MAP Kinases; D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases