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Acute Leukemias

Activity patterns of proteasome subunits reflect bortezomib sensitivity of hematologic malignancies and are variable in primary human leukemia cells

Leukemia volume 21, pages 84–92 (2007)Cite this article

Abstract

Proteasomal proteolysis relies on the activity of six catalytically active proteasomal subunits (β1, β2, β5, β1i, β2i and β5i). Applying a functional proteomics approach, we used a recently developed activity-based, cell-permeable proteasome-specific probe that for the first time allows differential visualization of individual active proteasomal subunits in intact primary cells. In primary leukemia samples, we observed remarkable variability in the amounts of active β1/1i-, β2/2i- and β5/5i-type of subunits, contrasting with their constant protein expression. Bortezomib inhibited β5- and β1-type, but to a lesser extend β2-type of subunits in live primary cells in vitro and in vivo. When we adapted the bortezomib-sensitive human acute myeloid leukemia cell line HL-60 to bortezomib 40 nM (HL-60a), proteasomal activity profiling revealed an upregulation of active subunits, and residual β1/β5-type of activity could be visualized in the presence of bortezomib 20 nM, in contrast to control cells. In a panel of cell lines from hematologic malignancies, the ratio between β2-type and (β1+β5)-type of active proteasomal polypeptides mirrored different degrees of bortezomib sensitivity. We thus conclude that the proteasomal activity profile varies in primary leukemia cells, and that the pattern of proteasomal subunit activity influences the sensitivity of hematologic malignancies toward bortezomib.

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Acknowledgements

This work was supported by the Deutsche Krebshilfe (project 106739), the fortune-Programm at the University of Tübingen, the Sonderforschungsbereich 685 (project B2) and the Netherlands Organization for Scientific Research (NWO) to HO.

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Author notes

  1. M Kraus and T Rückrich: These authors contributed equally to this work.

Authors and Affiliations

  1. The Department of Medicine II, University of Tübingen, Tübingen, Germany

    M Kraus, T Rückrich, M Reich, J Gogel & C Driessen

  2. The Department of Medicine IV, University of Tübingen, Tübingen, Germany

    A Beck

  3. ZBiT/Proteomics, University of Tübingen, Tübingen, Germany

    W Kammer

  4. Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    C R Berkers, D Burg & H Ovaa

  5. Department of Chemistry, Leiden University, Leiden, The Netherlands

    H Overkleeft

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  1. M Kraus
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  2. T Rückrich
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  11. C Driessen
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Corresponding author

Correspondence to C Driessen.

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Kraus, M., Rückrich, T., Reich, M. et al. Activity patterns of proteasome subunits reflect bortezomib sensitivity of hematologic malignancies and are variable in primary human leukemia cells. Leukemia 21, 84–92 (2007). https://doi.org/10.1038/sj.leu.2404414

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  • DOI: https://doi.org/10.1038/sj.leu.2404414

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