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

Summary 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.