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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 n. 16, 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
ISSN
2020 Impact Factor: 22.113
2015 SCImago Journal Rankings: 6.395
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHe, BL-
dc.contributor.authorShi, X-
dc.contributor.authorMan, CH-
dc.contributor.authorMa, CH-
dc.contributor.authorEkker, SC-
dc.contributor.authorChow, CH-
dc.contributor.authorSo, CW-
dc.contributor.authorChoi, WL-
dc.contributor.authorZhang, W-
dc.contributor.authorZhang, Y-
dc.contributor.authorLeung, AYH-
dc.date.accessioned2014-07-22T01:05:01Z-
dc.date.available2014-07-22T01:05:01Z-
dc.date.issued2014-
dc.identifier.citationBlood, 2014, v. 123 n. 16, p. 2518-2529-
dc.identifier.issn0006-4971-
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.-
dc.languageeng-
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlood-
dc.titleFunctions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia-
dc.typeArticle-
dc.identifier.emailMan, CH: csman729@hku.hk-
dc.identifier.emailMa, CH: alvinma@hku.hk-
dc.identifier.emailChow, CH: chowch@hku.hk-
dc.identifier.emailChoi, WL: choiwl@hkucc.hku.hk-
dc.identifier.emailLeung, AYH: ayhleung@hku.hk-
dc.identifier.authorityMan, CH=rp02543-
dc.identifier.authorityMa, CH=rp01810-
dc.identifier.authorityChoi, WL=rp00247-
dc.identifier.authorityLeung, AYH=rp00265-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1182/blood-2013-02-486688-
dc.identifier.pmid24591202-
dc.identifier.pmcidPMC4017313-
dc.identifier.scopuseid_2-s2.0-84901819794-
dc.identifier.hkuros231491-
dc.identifier.hkuros276265-
dc.identifier.volume123-
dc.identifier.issue16-
dc.identifier.spage2518-
dc.identifier.epage2529-
dc.identifier.isiWOS:000335894500019-
dc.publisher.placeUnited States-
dc.identifier.issnl0006-4971-

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