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

Bai Liang He; Xiangguo Shi; Cheuk Him Man; Alvin C.H. Ma; Stephen C. Ekker; Howard C.H. Chow; Chi Wai Eric So; William W.L. Choi; Wenqing Zhang; Yiyue Zhang; Anskar Y.H. Leung

doi:10.1182/blood-2013-02-486688

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

Bai Liang He, Xiangguo Shi, Cheuk Him Man, Alvin C.H. Ma, Stephen C. Ekker, Howard C.H. Chow, Chi Wai Eric So, William W.L. Choi, Wenqing Zhang, Yiyue Zhang, Anskar Y.H. Leung

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

FMS-like tyrosine kinase 3 (FLT3) is expressed in human hematopoietic stem and progenitor cells (HSPCs) 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% of patients and is associated with inferior clinical prognosis. TKD mutations (FLT3-TKD⁺) occur in 5% of 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 knockdown significantly reduced the expression of l-plastin (pan-leukocyte), csf1r, and mpeg1 (macrophage) as well as that of c-myb (definitive HSPCs), 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, albeitmodest, myeloid expansion resistant toAC220. This study provides novel insight into the role of flt3 during hematopoiesis and establishes a zebrafishmodel of FLT3-ITD⁺ and FLT3-TKD⁺ AML that may facilitate high-throughput screening of novel and personalized agents.

Original language	English (US)
Pages (from-to)	2518-2529
Number of pages	12
Journal	Blood
Volume	123
Issue number	16
DOIs	https://doi.org/10.1182/blood-2013-02-486688
State	Published - Apr 17 2014

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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@article{642e9e147bf14e7c8ca6114420f18eab,

title = "Functions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia",

abstract = "FMS-like tyrosine kinase 3 (FLT3) is expressed in human hematopoietic stem and progenitor cells (HSPCs) 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% of patients and is associated with inferior clinical prognosis. TKD mutations (FLT3-TKD+) occur in 5% of 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 knockdown significantly reduced the expression of l-plastin (pan-leukocyte), csf1r, and mpeg1 (macrophage) as well as that of c-myb (definitive HSPCs), 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, albeitmodest, myeloid expansion resistant toAC220. This study provides novel insight into the role of flt3 during hematopoiesis and establishes a zebrafishmodel of FLT3-ITD+ and FLT3-TKD+ AML that may facilitate high-throughput screening of novel and personalized agents.",

author = "He, {Bai Liang} and Xiangguo Shi and Man, {Cheuk Him} and Ma, {Alvin C.H.} and Ekker, {Stephen C.} and Chow, {Howard C.H.} and So, {Chi Wai Eric} and Choi, {William W.L.} and Wenqing Zhang and Yiyue Zhang and Leung, {Anskar Y.H.}",

year = "2014",

month = apr,

day = "17",

doi = "10.1182/blood-2013-02-486688",

language = "English (US)",

volume = "123",

pages = "2518--2529",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "16",

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TY - JOUR

T1 - Functions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia

AU - He, Bai Liang

AU - Shi, Xiangguo

AU - Man, Cheuk Him

AU - Ma, Alvin C.H.

AU - Ekker, Stephen C.

AU - Chow, Howard C.H.

AU - So, Chi Wai Eric

AU - Choi, William W.L.

AU - Zhang, Wenqing

AU - Zhang, Yiyue

AU - Leung, Anskar Y.H.

PY - 2014/4/17

Y1 - 2014/4/17

N2 - FMS-like tyrosine kinase 3 (FLT3) is expressed in human hematopoietic stem and progenitor cells (HSPCs) 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% of patients and is associated with inferior clinical prognosis. TKD mutations (FLT3-TKD+) occur in 5% of 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 knockdown significantly reduced the expression of l-plastin (pan-leukocyte), csf1r, and mpeg1 (macrophage) as well as that of c-myb (definitive HSPCs), 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, albeitmodest, myeloid expansion resistant toAC220. This study provides novel insight into the role of flt3 during hematopoiesis and establishes a zebrafishmodel of FLT3-ITD+ and FLT3-TKD+ AML that may facilitate high-throughput screening of novel and personalized agents.

AB - FMS-like tyrosine kinase 3 (FLT3) is expressed in human hematopoietic stem and progenitor cells (HSPCs) 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% of patients and is associated with inferior clinical prognosis. TKD mutations (FLT3-TKD+) occur in 5% of 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 knockdown significantly reduced the expression of l-plastin (pan-leukocyte), csf1r, and mpeg1 (macrophage) as well as that of c-myb (definitive HSPCs), 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, albeitmodest, myeloid expansion resistant toAC220. This study provides novel insight into the role of flt3 during hematopoiesis and establishes a zebrafishmodel of FLT3-ITD+ and FLT3-TKD+ AML that may facilitate high-throughput screening of novel and personalized agents.

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U2 - 10.1182/blood-2013-02-486688

DO - 10.1182/blood-2013-02-486688

M3 - Article

C2 - 24591202

AN - SCOPUS:84901819794

SN - 0006-4971

VL - 123

SP - 2518

EP - 2529

JO - Blood

JF - Blood

IS - 16

ER -

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

Abstract

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