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The fusion protein AML1-ETO in acute myeloid leukemia with translocation t(8;21) induces c-jun protein expression via the proximal AP-1 site of the c-jun promoter in an indirect, JNK-dependent manner

Oncogene volume 22, pages 5646–5657 (2003)Cite this article

Abstract

Overexpression of proto-oncogene c-jun and constitutive activation of the Jun N-terminal kinase (JNK) signaling pathway have been implicated in the leukemic transformation process. However, c-jun expression and the role of the JNK signaling pathway have not been investigated in primary acute myeloid leukemia (AML) cells with frequently observed balanced rearrangements such as t(8;21). In the present study, we report elevated c-jun mRNA expression in AML patient bone marrow cells with t(8;21), t(15;17) or inv(16), and a high correlation in mRNA expression levels of AML1-ETO and c-jun within t(8;21)-positive AML patient cells. In myeloid U937 cells, c-jun mRNA and protein expression increase upon inducible expression of AML1-ETO. AML1-ETO transactivates the human c-jun promoter through the proximal activator protein (AP-1) site by activating the JNK pathway. Overexpression of JNK-inhibitor JIP-1 and chemical JNK inhibitors reduce the transactivation capacity of AML1-ETO on the c-jun promoter and the proapoptotic function of AML1-ETO in U937 cells. An autocrine mechanism involving granulocyte-colony stimulating factor (G-CSF) and G-CSF receptor (G-CSF-R) might participate in AML1-ETO mediated JNK-signaling, because AML1-ETO induces G-CSF and G-CSF-R expression, and G-CSF-R-neutralizing antibodies reduce AML1-ETO-induced JNK phosphorylation. These data suggest a model in which AML1-ETO induces proto-oncogene c-jun expression via the proximal AP-1 site of the c-jun promoter in a JNK-dependent manner.

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Acknowledgements

We thank Pier Guiseppe Pelicci for providing us with the U937 cell line with Zn2+ inducible expression of AML1-ETO, and Wayne Vedeckis and Xiao-Fan Wang for the c-jun promoter constructs. This study was supported by a grant from the ‘Deutsche José Carreras Leukaemie-Stiftung’ to AE (DJCLS-99/NAT-1), by a grant from the DFG (German Research Foundation) to GB (2042/2-1) and by a grant from the NIH (CA41456) to DGT. Parts of this work were performed within the thesis of Michael Franzen.

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Authors and Affiliations

  1. Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany

    Annika Elsässer, Michael Franzen, Alexander Kohlmann, Martin Weisser, Susanne Schnittger, Claudia Schoch, Venkateshwar A Reddy, Wolfgang Hiddemann & Gerhard Behre

  2. GSF-National Research Center for Environment and Health, Munich, D-81377, Germany

    Annika Elsässer, Michael Franzen, Alexander Kohlmann, Martin Weisser, Susanne Schnittger, Claudia Schoch, Venkateshwar A Reddy, Wolfgang Hiddemann & Gerhard Behre

  3. The Scripps Research Institute, La Jolla, MEM-L51, CA, USA

    Sebastian Burel & Dong-Er Zhang

  4. Institute of Human Genetics, Technical University and GSF-National Research Center for Environment and Health, Munich, 81377, Germany

    Marius Ueffing

  5. Harvard Institutes of Medicine, Harvard Medical School, Boston, 02115, MA, USA

    Daniel G Tenen

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  1. Annika Elsässer
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Correspondence to Gerhard Behre.

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Elsässer, A., Franzen, M., Kohlmann, A. et al. The fusion protein AML1-ETO in acute myeloid leukemia with translocation t(8;21) induces c-jun protein expression via the proximal AP-1 site of the c-jun promoter in an indirect, JNK-dependent manner. Oncogene 22, 5646–5657 (2003). https://doi.org/10.1038/sj.onc.1206673

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