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

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

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    He, B. L., Shi, X., Man, C. H., Ma, A. C. H., Ekker, S. C., Chow, H. C. H., So, C. W. E., Choi, W. W. L., Zhang, W., Zhang, Y., & 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