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Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells

Leukemia volume 18, pages 1964–1970 (2004)Cite this article

Abstract

In the present work we investigated the role and biological significance of mitogen activated protein kinases (MAPK) in B-cell chronic lymphocytic leukaemia (B-CLL). The MAPK p38 was constitutively activated in B-CLL, but not in normal peripheral B cells. In addition, we demonstrated that the upstream kinases of p38, MKK3/6 were also constitutively activated in B-CLL cells. Furthermore, we determined by EMSA that the p38 MAP kinase pathway was not linked to the constitutive high expression of NF-κB, a critical survival factor of B-CLL cells. Recently, it has been shown that serum levels of angiogenic factors like VEGF, bFGF and MMP-9 are elevated in the serum of CLL patients and correlate with an unfavorable prognosis. We showed that the constitutive expression of MMP-9 was dependent on p38-activity and inhibition of p38 strongly downregulated MMP-9 expression. Coculture of B-CLL cells and stromal cells can protect spontaneous apoptosis of leukemic B cells. To determine the role of permanently activated p38 and MMP-9 expression, we cocultured B-CLL cells with bone marrow stromal cells. Survival of B-CLL cells on stroma was severely impaired when p38 was inhibited. Furthermore, blockade of MMP-9 activity also antagonized the antiapoptotic effect of stromal cells.

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Acknowledgements

This work was supported by a research grant from the Technical University of Munich (KKF 15-00) and a grant from the Deutsche Forschungsgemeinschaft DE 771.

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Author notes

  1. I Ringshausen

    Present address: Comprehensive Cancer Center, University of California, San Francisco, 2340 Sutter Street, Box 0-875, San Francisco, CA 94115, USA

Authors and Affiliations

  1. IIIrd Department of Medicine, Technical University of Munich, Munich, Germany

    I Ringshausen, T Dechow, F Schneller, K Weick, M Oelsner, C Peschel & T Decker

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  1. I Ringshausen
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Correspondence to I Ringshausen.

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Ringshausen, I., Dechow, T., Schneller, F. et al. Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells. Leukemia 18, 1964–1970 (2004). https://doi.org/10.1038/sj.leu.2403544

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