SPI-1 PU.1 TRANSGENIC MICE DEVELOP MULTISTEP ERYTHROLEUKEMIAS/

Insertional mutagenesis of the spi-1 gene is associated with the emerg ence of malignant proerythroblasts during Friend virus-induced acute e rythroleukemia, To determine the role of spi-1/PU.1 in the genesis of leukemia, we generated spi-1 transgenic mice, In one founder line the transgene was overexpressed as an unexpected-size transcript in variou s mouse tissues, Homozygous transgenic animals gave rise to live-born offspring, but 50% of the animals developed a multistep erythroleukemi a within 1.5 to 6 months of birth whereas the remainder survived witho ut evidence of disease, At the onset of the disease, mice became sever ely anemic, Their hematopoietic tissues were massively invaded with no ntumorigenic proerythroblasts that express a high level of Spi-1 prote in. These transgenic proerythroblasts are partially blocked in differe ntiation and strictly dependent on erythropoietin for their proliferat ion both in vivo and in vitro, A complete but transient regression of the disease was observed after erythrocyte transfusion, suggesting tha t the constitutive expression of spi-1 is related to the block of the differentiation of erythroid precursors. At relapse, erythropoietin-in dependent malignant proerythroblasts arose, Growth factor autonomy cou ld be partially explained by the autocrine secretion of erythropoietin ; however, other genetic events appear to be necessary to confer the f ull malignant phenotype, These results reveal that overexpression of s pi-1 is essential for malignant erythropoiesis and does not alter othe r hematopoietic lineages.