title: NUP98-HOXA9-transgenic zebrafish develop a myeloproliferative neoplasm and provide new insight into mechanisms of myeloid leukaemogenesis.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: A Michael
authors.initials: AM
authors.lastname: Forrester
authors.forename: Clemens
authors.initials: C
authors.lastname: Grabher
authors.forename: Eileen R
authors.initials: ER
authors.lastname: McBride
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Boyd
authors.forename: Märta H
authors.initials: MH
authors.lastname: Vigerstad
authors.forename: Alexander
authors.initials: A
authors.lastname: Edgar
authors.forename: Fui-Boon
authors.initials: FB
authors.lastname: Kai
authors.forename: Sahar I
authors.initials: SI
authors.lastname: Da'as
authors.forename: Elspeth
authors.initials: E
authors.lastname: Payne
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Jason N
authors.initials: JN
authors.lastname: Berman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D002453:Cell Cycle; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004249:DNA Damage; D050982:GATA1 Transcription Factor / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D015973:Gene Expression Regulation, Leukemic; D017930:Genes, Reporter; D006410:Hematopoiesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics* / Q000473:pathology; D007953:Leukemia, Radiation-Induced / Q000235:genetics / Q000473:pathology; D022423:Myeloid Cells / Q000473:pathology* / Q000528:radiation effects; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics; D019076:Transgenes; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000502:physiology; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050982:GATA1 Transcription Factor; D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D029961:Zebrafish Proteins; D000099232:Proto-Oncogene Protein Spi-1; C400441:NUP98-HOXA9 fusion protein, human; C494691:gata1a protein, zebrafish