NUP98-HOXA9-transgenic zebrafish develop a myeloproliferative neoplasm and provide new insight into mechanisms of myeloid leukaemogenesis

Forrester, A.M., Grabher, C., McBride, E.R., Boyd, E.R., Vigerstad, M.H., Edgar, A., Kai, F.B., Da'as, S.I., Payne, E., Look, A.T., and Berman, J.N.
British journal of haematology   155(2): 167-81 (Journal)
Registered Authors
Berman, Jason, Boyd, Ellen, Da'as, Sahar, Forrester, Michael, Grabher, Clemens, Look, A. Thomas, Payne, Elspeth M. (Beth), Vigerstad, Marta
NUP98-HOXA9, acute myeloid leukaemia, myeloproliferative disease, zebrafish, apoptosis
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Apoptosis
  • Cell Cycle
  • Cell Lineage
  • Cell Transformation, Neoplastic/genetics*
  • DNA Damage
  • GATA1 Transcription Factor/physiology
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Leukemic
  • Genes, Reporter
  • Hematopoiesis/genetics
  • Homeodomain Proteins/genetics*
  • Homeodomain Proteins/physiology
  • Humans
  • Leukemia, Experimental/genetics*
  • Leukemia, Experimental/pathology
  • Leukemia, Radiation-Induced/genetics
  • Leukemia, Radiation-Induced/pathology
  • Myeloid Cells/pathology*
  • Myeloid Cells/radiation effects
  • Myeloproliferative Disorders/genetics*
  • Myeloproliferative Disorders/pathology
  • Nuclear Pore Complex Proteins/genetics*
  • Nuclear Pore Complex Proteins/physiology
  • Oncogene Proteins, Fusion/genetics*
  • Oncogene Proteins, Fusion/physiology
  • Phenotype
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins/genetics
  • Recombinant Fusion Proteins/physiology
  • Trans-Activators/genetics
  • Transgenes
  • Zebrafish/embryology
  • Zebrafish Proteins/physiology
21810091 Full text @ Br. J. Haematol.
NUP98-HOXA9 [t(7;11) (p15;p15)] is associated with inferior prognosis in de novo and treatment-related acute myeloid leukaemia (AML) and contributes to blast crisis in chronic myeloid leukaemia (CML). We have engineered an inducible transgenic zebrafish harbouring human NUP98-HOXA9 under the zebrafish spi1(pu.1) promoter. NUP98-HOXA9 perturbed zebrafish embryonic haematopoiesis, with upregulated spi1expression at the expense of gata1a. Markers associated with more differentiated myeloid cells, lcp1, lyz, and mpx were also elevated, but to a lesser extent than spi1, suggesting differentiation of early myeloid progenitors may be impaired by NUP98-HOXA9. Following irradiation, NUP98-HOXA9-expressing embryos showed increased numbers of cells in G2-M transition compared to controls and absence of a normal apoptotic response, which may result from an upregulation of bcl2. These data suggest NUP98-HOXA9-induced oncogenesis may result from a combination of defects in haematopoiesis and an aberrant response to DNA damage. Importantly, 23% of adult NUP98-HOXA9-transgenic fish developed a myeloproliferative neoplasm (MPN) at 19–23 months of age. In summary, we have identified an embryonic haematopoietic phenotype in a transgenic zebrafish line that subsequently develops MPN. This tool provides a unique opportunity for high-throughput in vivo chemical modifier screens to identify novel therapeutic agents in high risk AML.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes