Zebrafish Models of Cancer

Division Of Basic Sciences - Nci

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Abstract

We have a zebrafish with gata2a disrupted and are working to develop a zebrafish with gata2b disrupted. Leukemias have been induced in zebrafish primarily using a transgenic approach to express oncogenes.Known human leukemia translocations such as AML1-ETO have been shown to direct zebrafish hematopoiesis down the myeloid pathway at the expense of the lymphoid pathway. Recently, NUP98-HOXA9 transgenic zebrafish were shown to develop a myeloproliferative neoplasm. Since patients with haploinsufficiency of GATA2 develop MDS/AML as young to middle-aged adults, it may take a year or more for the transformation to MDS/AML in gata2a heterozygous zebrafish. We have carried out this type of analysis for our TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia. Whole fish histologic sections will be done on fish with abdominal masses looking for kidney hypertrophy and evidence of malignant infiltrates with myeloid morphology. If there is no evidence of MDS/AML in the gata2a zebrafish, we will generate a gata2b mutant fish using the zinc finger technology. We have obtained the zinc fingers for the generation of this mutant. The gata2a fish will also be bred to lines with a known tumor predisposition such as NUP98-HOXA9, P53 and brca2. brca2 is of particular interest since it appears that patients with mutations in GATA2 have a markedly increased incidence in breast cancer (D. Hickstein, S. Holland, unpublished).