Article: Methionine aminopeptidase 2 is required for HSC initiation and proliferation
| Title | Methionine aminopeptidase 2 is required for HSC initiation and proliferation |
|---|---|
| Authors | Ma, ACH1 Fung, TK1 Lin, RHC1 Chung, MIS1 Yang, D3 Ekker, SC2 Leung, AYH1 |
| Issue Date | 2011 |
| Publisher | American Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/ |
| Citation | Blood, 2011, v. 118 n. 20, p. 5448-5457 [How to Cite?] DOI: http://dx.doi.org/10.1182/blood-2011-04-350173 |
| 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 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 hithertoundescribed role of MetAP2 in definitive hematopoiesis and a possible link to non-canonical Wnt and ERK signaling. © 2011 by The American Society of Hematology. |
| ISSN | 0006-4971 2011 Impact Factor: 9.898 2011 SCImago Journal Rankings: 1.698 |
| DOI | http://dx.doi.org/10.1182/blood-2011-04-350173 |
| PubMed Central ID | PMC3342862 |
| References | References in Scopus |
| Grants | A novel role of methionine aminopeptidase 2 (MetAP-2) in the regulation of hematopoietic stem cell during definitive hematopoiesis |
| dc.contributor.author | Ma, ACH | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Fung, TK | ||||||
| dc.contributor.author | Lin, RHC | ||||||
| dc.contributor.author | Chung, MIS | ||||||
| dc.contributor.author | Yang, D | ||||||
| dc.contributor.author | Ekker, SC | ||||||
| dc.contributor.author | Leung, AYH | ||||||
| dc.date.accessioned | 2012-03-27T08:56:06Z | ||||||
| dc.date.available | 2012-03-27T08:56:06Z | ||||||
| dc.date.issued | 2011 | ||||||
| dc.description.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 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 hithertoundescribed role of MetAP2 in definitive hematopoiesis and a possible link to non-canonical Wnt and ERK signaling. © 2011 by The American Society of Hematology. | ||||||
| dc.description.grant | A novel role of methionine aminopeptidase 2 (MetAP-2) in the regulation of hematopoietic stem cell during definitive hematopoiesis | ||||||
| dc.description.grantcode | 103539 | ||||||
| dc.description.nature | link_to_OA_fulltext | ||||||
| dc.identifier.citation | Blood, 2011, v. 118 n. 20, p. 5448-5457 [How to Cite?] DOI: http://dx.doi.org/10.1182/blood-2011-04-350173 | ||||||
| dc.identifier.doi | http://dx.doi.org/10.1182/blood-2011-04-350173 | ||||||
| dc.identifier.epage | 5457 | ||||||
| dc.identifier.hkuros | 198873 | ||||||
| dc.identifier.isi | WOS:000297265400015
Funding Information: The work was supported by the General Research Fund (GRF; HKU 771110M) and an Innovative Collaborative Research Program from the LKS Faculty of Medicine, The University of Hong Kong. | ||||||
| dc.identifier.issn | 0006-4971 2011 Impact Factor: 9.898 2011 SCImago Journal Rankings: 1.698 | ||||||
| dc.identifier.issue | 20 | ||||||
| dc.identifier.pmcid | PMC3342862 | ||||||
| dc.identifier.pmid | 21937698 | ||||||
| dc.identifier.scopus | eid_2-s2.0-81555214651 | ||||||
| dc.identifier.spage | 5448 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/145873 | ||||||
| dc.identifier.volume | 118 | ||||||
| dc.language | eng | ||||||
| dc.publisher | American Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/ | ||||||
| dc.publisher.place | United States | ||||||
| dc.relation.ispartof | Blood | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.rights | This research was originally published in The Hematologist: ASH News and Reports. Author(s). Title. The Hematologist: ASH News and Reports. 2011; Vol 118, Issue 20: pp5448-pp5457. © the American Society of Hematology. | ||||||
| dc.subject.mesh | Aminopeptidases - genetics - metabolism - physiology | ||||||
| dc.subject.mesh | Angiogenesis Inhibitors - pharmacology | ||||||
| dc.subject.mesh | Glycoproteins - genetics - physiology | ||||||
| dc.subject.mesh | Hematopoietic Stem Cells - cytology - enzymology | ||||||
| dc.subject.mesh | Metalloendopeptidases - genetics - physiology | ||||||
| dc.title | Methionine aminopeptidase 2 is required for HSC initiation and proliferation | ||||||
| dc.type | Article |
Author Affiliations
- The University of Hong Kong Li Ka Shing Faculty of Medicine
- Mayo Clinic
- The University of Hong Kong