AN MII-AF9 FUSION GENE MADE BY HOMOLOGOUS RECOMBINATION CAUSES ACUTE-LEUKEMIA IN CHIMERIC MICE - A METHOD TO CREATE FUSION ONCOGENES

Homologous recombination in embryonal stem cells has been used to prod uce a fusion oncogene, thereby mimicking chromosomal translocations th at frequently result in formation of tumor-specific fusion oncogenes i n human malignancies. AF9 sequences were fused into the mouse MII gene so that expression of the MII-AF9 fusion gene occurred from endogenou s MII transcription control elements, as in t(9;11) found in human leu kemias. Chimeric mice carrying the fusion gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread act ivity of the MII promoter. Onset of perceptible disease was preceded b y expansion of ES cell derivatives in peripheral blood. This novel use of homologous recombination formally proves that chromosomal transloc ations contribute to malignancy and provides a general strategy to cre ate fusion oncogenes for studying their role in tumorigenesis.