Abstract
Activation of the spi-1/PU.1 proto-oncogene and loss of p53 function are genetic alterations associated with the emergence of Friend malignant erythroleukemic cells. To address the role of p53 during erythroleukemogenesis, spi-1 transgenic mice (spi-1-Tg) which develop erythroleukemia were bred with p53-deficient mice. Three classes of spi-1 transgenic mice differing in their 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 mice, erythroleukemic cells gave rise to growth factor-independent cell lines 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 genotypes. Unexpectedly, 50% of p53−/− spi-1-Tg erythroleukemic spleens generated cell lines that were strictly dependent upon erythropoietin (Epo) for proliferation, whereas the remainder proliferated independently of cytokines. Moreover, only 70% of these spleen cells were tumorigenic. These findings indicate that p53 germ-line deletion did not confer malignancy to spi-1-transgenic proerythroblasts. Moreover Epo independence and tumorigenicity appear as separable phenotypic characteristics revealing that the spi-1-Tg proerythroblasts progress towards malignancy through multiple oncogenic events.
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Acknowledgements
We thank Christel Guillouf for critical reading of the manuscript; Jean de Gunzburg and Jacques Camonis for valuable comments; Annie Rouchés and Patrice Ardouin for valuable assistance with the animals housed at the Institut Gustave Roussy. This work was supported in part by grants from the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche sur le Cancer, the Ligue de Paris de Recherche contre le Cancer and the Institut Curie (Paris, France). S Barnache was supported by a grant from the Ligue Nationale de Recherche contre le Cancer.
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Le Scolan, E., Wendling, F., Barnache, S. et al. Germ-line deletion of p53 reveals a multistage tumor progression in spi-1/PU.1 transgenic proerythroblasts. Oncogene 20, 5484–5492 (2001). https://doi.org/10.1038/sj.onc.1204708
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DOI: https://doi.org/10.1038/sj.onc.1204708