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

Br J Haematol. 2011 Oct;155(2):167-81. doi: 10.1111/j.1365-2141.2011.08810.x. Epub 2011 Aug 2.


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 spi1 expression 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.

Publication types

  • Research Support, Non-U.S. Gov't

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


  • GATA1 Transcription Factor
  • Homeodomain Proteins
  • NUP98-HOXA9 fusion protein, human
  • Nuclear Pore Complex Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Zebrafish Proteins
  • gata1a protein, zebrafish
  • proto-oncogene protein Spi-1