PUBLICATION
NUP98-HOXA9-transgenic zebrafish develop a myeloproliferative neoplasm and provide new insight into mechanisms of myeloid leukaemogenesis
- Authors
- 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.
- ID
- ZDB-PUB-110811-2
- Date
- 2011
- Source
- 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
- Keywords
- 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
- PubMed
- 21810091 Full text @ Br. J. Haematol.
Citation
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. (2011) NUP98-HOXA9-transgenic zebrafish develop a myeloproliferative neoplasm and provide new insight into mechanisms of myeloid leukaemogenesis. British journal of haematology. 155(2):167-81.
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 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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping