Abstract
Deregulated expression of the myc-family of oncogenes in hematopoietic and other cell types plays an important role in tumorigenesis, and results in increased proliferative potential and block of cellular differentiation. We have previously shown that IFN-γ restores phorbol ester-induced differentiation and cell cycle arrest in v-myc transformed human U-937 monoblasts. To investigate whether other cytokine signals could also abrogate such a block, IL-1, IL-3, IL-4, IL-6, IL-7, IL-10, IL-11, LIF, oncostatin M, M-CSF, G-CSF and GM-CSF, and TGFβ1, TNF-α, IFN-α were examined. We show that GM-CSF and IL-6, in combination with the phorbol ester 12-O-tetradecanoyl-phorbol acetate (TPA), restored differentiation and cell cycle arrest. In contrast, treatment by TGFβ1 ± TPA resulted in an efficient G1/G0 arrest, but did not appear to induce terminal differentiation. Restoration of differentiation and cell cycle arrest was accomplished despite maintained expression of the v-Myc protein. Our results show that the cytokine-induced signals reduced Myc-dependent transcription of an artificial target promoter/reporter gene construct, correlating in most, but not all, cases with decreased association of v- and c-Myc with its essential partner, Max. Thus, cytokine-induced signals may counteract the activity of deregulated Myc, and contribute to the normalization of differentiation, arrest in the G1/G0 phase of the cell cycle, or both.
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Acknowledgements
We thank Nina Hult for important contributions during the early phase of this study and Inger Karlberg for excellent technical assistance. We also thank Drs GR Adolf, S Clark, S Gillis, T Kishimoto and M Sporn for generous gifts of cytokines. This work was supported by grants from the Swedish Cancer Society, the Children Cancer Foundation of Sweden, the von Kantzow Foundation, and the Lovisa and Thielmann Foundation.
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Öberg, F., Wu, S., Bahram, F. et al. Cytokine-induced restoration of differentiation and cell cycle arrest in v-Myc transformed U-937 monoblasts correlates with reduced Myc activity. Leukemia 15, 217–227 (2001). https://doi.org/10.1038/sj.leu.2402025
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DOI: https://doi.org/10.1038/sj.leu.2402025