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Article: Functions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia.

TitleFunctions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia.
Authors
Issue Date2014
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
Blood, 2014, v. 123, p. 2518-2529 How to Cite?
AbstractFMS-like tyrosine kinase 3 (FLT3) is expressed in human hematopoietic stem and progenitor cells (HSPC) but its role during embryogenesis is unclear. In acute myeloid leukemia (AML), internal tandem duplication (ITD) of FLT3 at the juxtamembrane (JMD) and tyrosine kinase (TKD) domains (FLT3-ITD+) occurs in 30% patients and is associated with inferior clinical prognosis. TKD mutations (FLT3-TKD+) occur in 5% cases. We made use of zebrafish to examine the role of flt3 in developmental hematopoiesis and model human FLT3-ITD+ and FLT3-TKD+ AML. Zebrafish flt3 JMD and TKD were remarkably similar to their mammalian orthologs. Morpholino knock-down significantly reduced the expression of l-plastin (pan-leukocyte), csf1r and mpeg1 (macrophage) as well as that of c-myb (definitive HSPC), lck and rag1 (T-lymphocyte). Expressing human FLT3-ITD in zebrafish embryos resulted in expansion and clustering of myeloid cells (pu.1+, mpo+, and cebpα+) which were ameliorated by AC220 and associated with stat5, erk1/2, and akt phosphorylation. Human FLT3-TKD (D835Y) induced significant, albeit modest, myeloid expansion resistant to AC220. This study provides novel insight to the role of flt3 during hematopoiesis and establishes a zebrafish model of FLT3-ITD+ and FLT3-TKD+ AML that may facilitate high throughput screening of novel and personalized agents.
Persistent Identifierhttp://hdl.handle.net/10722/199169
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHE, Ben_US
dc.contributor.authorSHI, Xen_US
dc.contributor.authorMan, CHen_US
dc.contributor.authorMa, CHen_US
dc.contributor.authorEkker, SCen_US
dc.contributor.authorChow, CHen_US
dc.contributor.authorSo, CWen_US
dc.contributor.authorChoi, WLen_US
dc.contributor.authorZhang, Wen_US
dc.contributor.authorZhang, Yen_US
dc.contributor.authorLeung, AYHen_US
dc.date.accessioned2014-07-22T01:05:01Z-
dc.date.available2014-07-22T01:05:01Z-
dc.date.issued2014en_US
dc.identifier.citationBlood, 2014, v. 123, p. 2518-2529en_US
dc.identifier.urihttp://hdl.handle.net/10722/199169-
dc.description.abstractFMS-like tyrosine kinase 3 (FLT3) is expressed in human hematopoietic stem and progenitor cells (HSPC) but its role during embryogenesis is unclear. In acute myeloid leukemia (AML), internal tandem duplication (ITD) of FLT3 at the juxtamembrane (JMD) and tyrosine kinase (TKD) domains (FLT3-ITD+) occurs in 30% patients and is associated with inferior clinical prognosis. TKD mutations (FLT3-TKD+) occur in 5% cases. We made use of zebrafish to examine the role of flt3 in developmental hematopoiesis and model human FLT3-ITD+ and FLT3-TKD+ AML. Zebrafish flt3 JMD and TKD were remarkably similar to their mammalian orthologs. Morpholino knock-down significantly reduced the expression of l-plastin (pan-leukocyte), csf1r and mpeg1 (macrophage) as well as that of c-myb (definitive HSPC), lck and rag1 (T-lymphocyte). Expressing human FLT3-ITD in zebrafish embryos resulted in expansion and clustering of myeloid cells (pu.1+, mpo+, and cebpα+) which were ameliorated by AC220 and associated with stat5, erk1/2, and akt phosphorylation. Human FLT3-TKD (D835Y) induced significant, albeit modest, myeloid expansion resistant to AC220. This study provides novel insight to the role of flt3 during hematopoiesis and establishes a zebrafish model of FLT3-ITD+ and FLT3-TKD+ AML that may facilitate high throughput screening of novel and personalized agents.en_US
dc.languageengen_US
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/en_US
dc.relation.ispartofBlooden_US
dc.rightsThis research was originally published in The Hematologist: ASH News and Reports. Author(s). Title. The Hematologist: ASH News and Reports. Year;Vol,Issue:pp-pp. © the American Society of Hematology.en_US
dc.titleFunctions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia.en_US
dc.typeArticleen_US
dc.identifier.emailMan, CH: csman729@hku.hken_US
dc.identifier.emailMa, CH: alvinma@hku.hken_US
dc.identifier.emailChow, CH: chowch@hku.hken_US
dc.identifier.emailChoi, WL: choiwl@hkucc.hku.hken_US
dc.identifier.emailLeung, AYH: ayhleung@hku.hken_US
dc.identifier.authorityMa, CH=rp01810en_US
dc.identifier.authorityChoi, WL=rp00247en_US
dc.identifier.authorityLeung, AYH=rp00265en_US
dc.identifier.doi10.1182/blood-2013-02-486688en_US
dc.identifier.pmid24591202-
dc.identifier.hkuros231491en_US
dc.identifier.volume123en_US
dc.identifier.spage2518en_US
dc.identifier.epage2529en_US
dc.identifier.isiWOS:000335894500019-
dc.publisher.placeUSAen_US

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