Abstract
Cancer is a multi-step, multi-genetic event. Whether oncogenic mutations cooperate with one another to transform cells and how is not well understood. The Friend murine retroviral erythroleukemia model involves mitogenic activation of the erythropoietin receptor (EpoR) by the virus env gene (F-gp55), aberrant over-expression of the transcription factor PU.1, and inactivating mutations in p53. In this report we demonstrate that concurrent expression of F-gp55 and PU.1 in erythroid target cells, in vivo, cooperate to accelerate erythroleukemia induction. Early in the disease, prior to the detection of clonal leukemic cells, activation of the EpoR by F-gp55, but not erythropoietin, resulted in transcriptional upregulation of PU.1 through a trans regulatory mechanism. This could occur in the absence of an integrated provirus within the PU.1 gene locus. The regulation of PU.1 transcription in established erythroleukemia cell lines differed depending upon the level of PU.1 protein present. Our results suggest that the action of F-gp55 contributes to both early and late stages of Friend erythroleukemia and that persistence of F-gp55 expression may be required not only to initiate erythroleukemia but to also maintain erythroleukemia following Friend virus infection.
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Acknowledgements
We would like to thank Dr Dan Tenen (Harvard Medical School, Boston MA, USA) for generously providing mouse PU.1 promoter luciferase plasmids, and helpful comments. Drs J Ghysdael and S Ruscetti for helpful comments. Dr T Yamada, Sasaki Institute, Tokyo for providing us with MEL-B8/3 cells. This work was supported by the NIH (R01 CA77447) and the Gillson Longenbaugh foundation (to SSW), and from the Association for International Cancer Research, the American Heart Association (9940116N), the Edward Mallinckrodt Jr. Foundation, and the NIH (RO1 CA75315) (to GD Longmore). GD Longmore is an Established Investigator of the American Heart Association.
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Afrikanova, I., Yeh, E., Bartos, D. et al. Oncogene cooperativity in Friend erythroleukemia: erythropoietin receptor activation by the env gene of SFFV leads to transcriptional upregulation of PU.1, independent of SFFV proviral insertion. Oncogene 21, 1272–1284 (2002). https://doi.org/10.1038/sj.onc.1205183
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DOI: https://doi.org/10.1038/sj.onc.1205183
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