THE ACUTE PROMYELOCYTIC LEUKEMIA PML-RAR-ALPHA PROTEIN INDUCES HEPATIC PRENEOPLASTIC AND NEOPLASTIC LESIONS IN TRANSGENIC MICE

The PML-RAR alpha hybrid protein generated by the t(15;17) translocati on in acute promyelocytic leukemia (APL) is thought to play a central role in the oncogenic process. However, analysis of the oncogenic acti vity of the fusion protein in tissue culture assays or in mice has bee n hampered by its apparent toxicity in multiple murine cells. To circu mvent this problem, we generated an inducible line of transgenic mice, MT135, in which the expression of PML-RAR alpha is driven by the meta llothionein promoter. After 5 days zinc stimulation, 27 out of 54 mice developed hepatic preneoplasia and neoplasia including foci of basoph ilic hepatocytes, dysplasia and carcinoma with a significantly higher incidence of lesions in females than in males. The rapid onset of live r pathologies was dependent on overexpression of the transgene since i t was not detected in noninduced transgenic animals of the same age. T he PML-RAR alpha protein was always present in altered tissues at much higher levels than in the surrounding normal liver tissues. In additi on, overexpression of PML-RAR alpha resulted in a strong proliferative response in the hepatocytes. We conclude that overexpression of PML-R AR alpha deregulates cell proliferation and can induce tumorigenic cha nges in vivo.