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

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)2518-2529
Number of pages12
JournalBlood
Volume123
Issue number16
DOIs
StatePublished - Apr 17 2014

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Hematopoiesis
Zebrafish
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Hematopoietic Stem Cells
Morpholinos
Phosphorylation
T-cells
Macrophages
Myeloid Cells
Embryonic Development
Cluster Analysis
Screening
Leukocytes
Embryonic Structures
Throughput
T-Lymphocytes
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

He, B. L., Shi, X., Man, C. H., Ma, A. C. H., Ekker, S. C., Chow, H. C. H., ... Leung, A. Y. H. (2014). Functions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia. Blood, 123(16), 2518-2529. https://doi.org/10.1182/blood-2013-02-486688

Functions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia. / He, Bai Liang; Shi, Xiangguo; Man, Cheuk Him; Ma, Alvin C H; Ekker, Stephen C; Chow, Howard C H; So, Chi Wai Eric; Choi, William W L; Zhang, Wenqing; Zhang, Yiyue; Leung, Anskar Y H.

In: Blood, Vol. 123, No. 16, 17.04.2014, p. 2518-2529.

Research output: Contribution to journalArticle

He, BL, Shi, X, Man, CH, Ma, ACH, Ekker, SC, Chow, HCH, So, CWE, Choi, WWL, Zhang, W, Zhang, Y & Leung, AYH 2014, 'Functions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia', Blood, vol. 123, no. 16, pp. 2518-2529. https://doi.org/10.1182/blood-2013-02-486688
He, Bai Liang ; Shi, Xiangguo ; Man, Cheuk Him ; Ma, Alvin C H ; Ekker, Stephen C ; Chow, Howard C H ; So, Chi Wai Eric ; Choi, William W L ; Zhang, Wenqing ; Zhang, Yiyue ; Leung, Anskar Y H. / Functions of flt3 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia. In: Blood. 2014 ; Vol. 123, No. 16. pp. 2518-2529.
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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.",
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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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