Germ-line deletion of p53 reveals a multistage tumor progression in spi-1/PU.1 transgenic proerythroblasts

Activation of the spi-1/PU.1 proto-oneogene and loss of p53 function are ge netic alterations associated with the emergence of Friend malignant erythro leukemic cells. To address the role of p53 during erythroleukemogenesis, sp i-1 transgenic mice (spi-1-Tg) which develop erythroleukemia were bred with p53-deficient mice. Three classes of spi-1 transgenic mice differing in th eir p53 functional status (p53(+/+), p53(+/-) and p53(-/-)) were generated. These mice developed a unique pattern of erythroleukemia. In wild-type p53 spi-1-Tg mice, none of the primary erythroleukemic spleen cells displayed autonomous growth in vitro and in vivo. In contrast, in p53(+/-) spi-1-Tg m ice, erythroleukemic cells gave rise to growth factor-independent cell line s and generated tumors in vivo. Malignancy was associated with loss of the wild-type p53 allele. The p53(-/-) spi-1-Tg mice developed erythroleukemia with a total incidence and a reduced latency compared to the two other geno types. Unexpectedly, 50% of p53(-/-) spi-1-Tg erythroleukemic spleens gener ated cell lines that were strictly dependent upon erythropoietin (Epo) for proliferation, whereas the remainder proliferated independently of cytokine s. Moreover, only 70% of these spleen cells were tumorigenic. These finding s indicate that p53 germ-line deletion did not confer malignancy to spi-1-t ransgenic proerythroblasts. Moreover Epo independence and tumorigenicity ap pear as separable phenotypic characteristics revealing that the spi-1-Tg pr oerythroblasts progress towards malignancy through multiple oncogenic event s.