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Article: A novel zebrafish jak2a V581F model shared features of human JAK2 V617F polycythemia vera

TitleA novel zebrafish jak2a V581F model shared features of human JAK2 V617F polycythemia vera
Authors
Issue Date2009
PublisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/exphem
Citation
Experimental Hematology, 2009, v. 37 n. 12, p. 1379-1386.e4 How to Cite?
AbstractObjective: The Janus kinase 2 (JAK2) is important for embryonic primitive hematopoiesis. A gain-of-function JAK2 (JAK2 V617F) mutation in human is pathogenetically linked to polycythemia vera (PV). In this study, we generated a zebrafish ortholog of human JAK2 V617F (referred herewith jak2a V581F) by site-directed mutagenesis and examined its relevance as a model of human PV. Materials and Methods: Zebrafish embryos at one-cell stage were injected with jak2a V581F mRNA (200pg/embryo). In some experiments, the embryos were treated with a specific JAK2 inhibitor, TG101209. The effects of jak2a stimulation on hematopoiesis, jak/stat signaling, and erythropoietin signaling were evaluated at 18-somites. Results: Injection with jak2a V581F mRNA significantly increased erythropoiesis, as enumerated by flow cytometry based on gfp + population in dissociated Tg(gata1:gfp) embryos. The response was reduced by stat5.1 morpholino coinjection (control: 4.37% ± 0.08%; jak2a V581F injected: 5.71% ± 0.07%, coinjecting jak2a V581F mRNA and stat5.1 morpholino: 4.66% ± 0.13%; p < 0.01). jak2a V581F mRNA also upregulated gata1 (1.83 ± 0.08 fold; p = 0.005), embryonic α-hemoglobin (1.61 ± 0.12 fold; p = 0.049), and β-hemoglobin gene expression (1.65 ± 0.13-fold; p = 0.026) and increased stat5 phosphorylation. These responses were also ameliorated by stat5.1 morpholino coinjection or treatment with a specific JAK2 inhibitor, TG101209. jak2a V581F mRNA significantly reduced erythropoietin gene (0.24 ± 0.03 fold; p = 0.006) and protein expression (control: 0.633 ± 0.11; jak2a V581F mRNA: 0.222 ± 0.07 mIU/mL; p = 0.019). Conclusion: The zebrafish jak2a V581F model shared many features with human PV and might provide us with mechanistic insights of this disease. © 2009 ISEH - Society for Hematology and Stem Cells.
Persistent Identifierhttp://hdl.handle.net/10722/76558
ISSN
2015 Impact Factor: 2.303
2015 SCImago Journal Rankings: 1.341
ISI Accession Number ID
Funding AgencyGrant Number
General Research FundHKU 7520/06 M
HKU 770308 M
University of Hong Kong
Funding Information:

The project was supported by the General Research Fund (HKU 7520/06 M and HKU 770308 M) and a grant from the strategy research theme of cancer stem cells in the University of Hong Kong.

References

 

DC FieldValueLanguage
dc.contributor.authorMa, ACHen_HK
dc.contributor.authorFan, Aen_HK
dc.contributor.authorWard, ACen_HK
dc.contributor.authorLiongue, Cen_HK
dc.contributor.authorLewis, RSen_HK
dc.contributor.authorCheng, SHen_HK
dc.contributor.authorChan, PKen_HK
dc.contributor.authorYip, SFen_HK
dc.contributor.authorLiang, Ren_HK
dc.contributor.authorLeung, AYHen_HK
dc.date.accessioned2010-09-06T07:22:31Z-
dc.date.available2010-09-06T07:22:31Z-
dc.date.issued2009en_HK
dc.identifier.citationExperimental Hematology, 2009, v. 37 n. 12, p. 1379-1386.e4en_HK
dc.identifier.issn0301-472Xen_HK
dc.identifier.urihttp://hdl.handle.net/10722/76558-
dc.description.abstractObjective: The Janus kinase 2 (JAK2) is important for embryonic primitive hematopoiesis. A gain-of-function JAK2 (JAK2 V617F) mutation in human is pathogenetically linked to polycythemia vera (PV). In this study, we generated a zebrafish ortholog of human JAK2 V617F (referred herewith jak2a V581F) by site-directed mutagenesis and examined its relevance as a model of human PV. Materials and Methods: Zebrafish embryos at one-cell stage were injected with jak2a V581F mRNA (200pg/embryo). In some experiments, the embryos were treated with a specific JAK2 inhibitor, TG101209. The effects of jak2a stimulation on hematopoiesis, jak/stat signaling, and erythropoietin signaling were evaluated at 18-somites. Results: Injection with jak2a V581F mRNA significantly increased erythropoiesis, as enumerated by flow cytometry based on gfp + population in dissociated Tg(gata1:gfp) embryos. The response was reduced by stat5.1 morpholino coinjection (control: 4.37% ± 0.08%; jak2a V581F injected: 5.71% ± 0.07%, coinjecting jak2a V581F mRNA and stat5.1 morpholino: 4.66% ± 0.13%; p < 0.01). jak2a V581F mRNA also upregulated gata1 (1.83 ± 0.08 fold; p = 0.005), embryonic α-hemoglobin (1.61 ± 0.12 fold; p = 0.049), and β-hemoglobin gene expression (1.65 ± 0.13-fold; p = 0.026) and increased stat5 phosphorylation. These responses were also ameliorated by stat5.1 morpholino coinjection or treatment with a specific JAK2 inhibitor, TG101209. jak2a V581F mRNA significantly reduced erythropoietin gene (0.24 ± 0.03 fold; p = 0.006) and protein expression (control: 0.633 ± 0.11; jak2a V581F mRNA: 0.222 ± 0.07 mIU/mL; p = 0.019). Conclusion: The zebrafish jak2a V581F model shared many features with human PV and might provide us with mechanistic insights of this disease. © 2009 ISEH - Society for Hematology and Stem Cells.en_HK
dc.languageengen_HK
dc.publisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/exphemen_HK
dc.relation.ispartofExperimental Hematologyen_HK
dc.subject.meshJanus Kinase 2 - antagonists and inhibitors - genetics - metabolism-
dc.subject.meshMutation-
dc.subject.meshPolycythemia Vera - enzymology - genetics - pathology-
dc.subject.meshProtein-Tyrosine Kinases - antagonists and inhibitors - genetics - metabolism-
dc.subject.meshZebrafish Proteins - antagonists and inhibitors - genetics - metabolism-
dc.titleA novel zebrafish jak2a V581F model shared features of human JAK2 V617F polycythemia veraen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0301-472X&volume=37&issue=12&spage=1379&epage=1386, 1386.e1&date=2009&atitle=A+novel+zebrafish+jak2aV581F+model+shared+features+of+human+JAK2V617F+polycythemia+veraen_HK
dc.identifier.emailLiang, R:rliang@hku.hken_HK
dc.identifier.emailLeung, AYH:ayhleung@hku.hken_HK
dc.identifier.authorityLiang, R=rp00345en_HK
dc.identifier.authorityLeung, AYH=rp00265en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.exphem.2009.08.008en_HK
dc.identifier.pmid19772888-
dc.identifier.scopuseid_2-s2.0-70449337685en_HK
dc.identifier.hkuros169453en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-70449337685&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume37en_HK
dc.identifier.issue12en_HK
dc.identifier.spage1379en_HK
dc.identifier.epage1386.e4en_HK
dc.identifier.isiWOS:000272433100001-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridMa, ACH=15849157500en_HK
dc.identifier.scopusauthoridFan, A=35336410600en_HK
dc.identifier.scopusauthoridWard, AC=7402090618en_HK
dc.identifier.scopusauthoridLiongue, C=15843776700en_HK
dc.identifier.scopusauthoridLewis, RS=7404844655en_HK
dc.identifier.scopusauthoridCheng, SH=35145200500en_HK
dc.identifier.scopusauthoridChan, PK=7403498052en_HK
dc.identifier.scopusauthoridYip, SF=7102133678en_HK
dc.identifier.scopusauthoridLiang, R=26643224900en_HK
dc.identifier.scopusauthoridLeung, AYH=7403012668en_HK
dc.identifier.citeulike5822442-

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