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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Erythroid Precursor Cells / drug effects
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Erythroid Precursor Cells / metabolism
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Erythroid Precursor Cells / pathology
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Erythroid Precursor Cells / virology
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Erythropoietin / metabolism
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Erythropoietin / pharmacology
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Gene Expression Regulation, Neoplastic* / drug effects
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Humans
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Interleukin-3 / pharmacology
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Leukemia, Erythroblastic, Acute / genetics*
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Leukemia, Erythroblastic, Acute / metabolism
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Leukemia, Erythroblastic, Acute / virology
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Mice
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Oncogenes / genetics*
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Erythropoietin / metabolism*
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Signal Transduction / drug effects
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Spleen Focus-Forming Viruses / genetics*
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Spleen Focus-Forming Viruses / physiology
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Time Factors
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Transcription, Genetic
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Tumor Cells, Cultured
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Up-Regulation
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Viral Envelope Proteins / genetics
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Viral Envelope Proteins / metabolism*
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Virus Integration*
Substances
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Interleukin-3
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Erythropoietin
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Trans-Activators
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Viral Envelope Proteins
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glycoprotein gp55, Friend spleen focus-forming virus
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proto-oncogene protein Spi-1
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Erythropoietin