A novel zebrafish jak2aV581F model shared features of human JAK2V617F polycythemia vera

Chun Hang Ma, August Fan, Alister C. Ward, Clifford Liongue, Rowena S. Lewis, Suk H. Cheng, P. K. Chan, Sze Fai Yip, Raymond Liang, Anskar Y H Leung

Research output: Journal article publicationJournal articleAcademic researchpeer-review

22 Citations (Scopus)

Abstract

Objective: The Janus kinase 2 (JAK2) is important for embryonic primitive hematopoiesis. A gain-of-function JAK2 (JAK2V617F) mutation in human is pathogenetically linked to polycythemia vera (PV). In this study, we generated a zebrafish ortholog of human JAK2V617F(referred herewith jak2aV581F) by site-directed mutagenesis and examined its relevance as a model of human PV. Materials and Methods: Zebrafish embryos at one-cell stage were injected with jak2aV581FmRNA (200pg/embryo). In some experiments, the embryos were treated with a specific JAK2 inhibitor, TG101209. The effects of jak2a stimulation on hematopoiesis, jak/stat signaling, and erythropoietin signaling were evaluated at 18-somites. Results: Injection with jak2aV581FmRNA significantly increased erythropoiesis, as enumerated by flow cytometry based on gfp+population in dissociated Tg(gata1:gfp) embryos. The response was reduced by stat5.1 morpholino coinjection (control: 4.37% ± 0.08%; jak2aV581Finjected: 5.71% ± 0.07%, coinjecting jak2aV581FmRNA and stat5.1 morpholino: 4.66% ± 0.13%; p < 0.01). jak2aV581FmRNA also upregulated gata1 (1.83 ± 0.08 fold; p = 0.005), embryonic α-hemoglobin (1.61 ± 0.12 fold; p = 0.049), and β-hemoglobin gene expression (1.65 ± 0.13-fold; p = 0.026) and increased stat5 phosphorylation. These responses were also ameliorated by stat5.1 morpholino coinjection or treatment with a specific JAK2 inhibitor, TG101209. jak2aV581FmRNA significantly reduced erythropoietin gene (0.24 ± 0.03 fold; p = 0.006) and protein expression (control: 0.633 ± 0.11; jak2aV581FmRNA: 0.222 ± 0.07 mIU/mL; p = 0.019). Conclusion: The zebrafish jak2aV581Fmodel shared many features with human PV and might provide us with mechanistic insights of this disease.
Original languageEnglish
JournalExperimental Hematology
Volume37
Issue number12
DOIs
Publication statusPublished - 1 Dec 2009
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology

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