MYST3/NCOA2-Induced Acute Myeloid Leukemia in Transgenic Fish

The MYST3/NCOA2 (MOZ/TIF2) fusion gene generated by the inv(8)(p11q13) chromosomal abnormality was described in a specific subgroup of acute myeloid leukemias (AML) that represents less than 5% of AML4/5. This abnormality fuses MYST3 (MOZ), a member of the MYST family of histone acetyl-transferases (HAT) to NCOA2 (TIF2), a member of the p160 HAT family. The transforming properties of MYST3/NCOA2 were demonstrated in mouse committed myeloid progenitors in vitro and in vivo. Hematopoiesis is very similar in zebrafish and in higher vertebrates. Homologues of a large number of genes involved in mammalian myelopoiesis were identified in this animal model. We have recently shown that ncoa2 (tif2) played a role in zebrafish primitive hematopoiesis. This animal also represents a model for investigating leukemogenesis. Transgenic expression of rag2-EGFP-mMyc or rag2-ICN1-EGFP induces a T-cell acute lymphoblastic leukemia (ALL) whereas transgenic expression of the ETV6/RUNX1 fusion gene induces a B-cell type ALL. We generated a transgenic zebrafish in which the MYST3/NCOA2 fusion gene was expressed under control of the spi1 (pu.1) promoter. An AML developed in two of 180 MYST3/NCOA2-EGFP-expressing embryos, 14 and 26 months after injection of the fusion gene in a one cell embryo, respectively. This leukemia was characterized by an extensive invasion of kidneys by myeloid blast cells. This model, which is the first zebrafish model of acute myeloid leukemia, demonstrates the oncogenic potency of MYST3/NCOA2 fusion gene.