Zebrafish are a surprisingly useful model system for studying cancer. They develop tumours that are similar to those in humans, yet they are genetically tractable. However, their use has been hampered by the lack of a stable line of transgenic, tumour-bearing animals. This obstacle has now been overcome by Thomas Look and colleagues, who have generated transgenic fish that express the mouse Myc oncogene and that succumb to T-cell leukaemia.

The Myc transgene — expressed behind the Rag2 promoter, which causes lymphoid-specific gene expression — was microinjected into wild-type zebrafish embryos, either with or without a green fluorescent protein (GFP) tag. Of the resulting fish, 5–6% developed tumours, regardless of whether GFP was present, and this proportion corresponded with the number of fish that expressed GFP if it was injected alone, which indicates that almost every fish that expresses the transgene develops cancer.

The fish developed tumours in the thymus, which is adjacent to the gills. Lymphoblasts had also infiltrated the kidney marrow — the site of definitive haematopoiesis in the fish — and several other sites. Quantitative analysis showed that six times more lymphoblasts were present in the kidney and spleen of the leukaemic fish than in wild-type fish.

Next, gene-expression profiles were analysed to determine the tumour lineage. Interestingly, T-cell-specific, but not B-cell-specific, genes were expressed in these tumours. Furthermore, two out of three of the examined tumours had clonal rearrangements in the zTcr-α gene, which both confirms the thymic origin and indicates that additional mutations are required for the leukaemia phenotype.

The transplantability of these tumours was assessed by intraperitoneally injecting leukaemic lymphoblasts into wild-type fish. Leukaemic cells were detectable at the site of injection within 7 days, and soon spread throughout the peritoneal cavity, eventually homing to the thymus.

The short life of these fish — due to cancer development — means that the line must be propagated by in vitro fertilization. Sperm taken from male leukaemic fish were used to fertilize eggs from wild-type females, and the resultant offspring developed leukaemia within 4–6 weeks. The use of regulatable promoters would solve this technical problem.

So, this cancer model is the first of its kind, and can now be used in forward screens that search for modifiers of the Myc-induced leukaemia phenotype. We await new discoveries with interest.