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Arsenic trioxide induces apoptosis preferentially in B-CLL cells of patients with unfavourable prognostic factors including del17p13

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Abstract

In the last decade, arsenic trioxide (As2O3) has been used very successfully to treat acute promyelocytic leukaemia (APL). Much less is known about the effectiveness of As2O3 in other neoplastic disorders. In this paper, we report that after 18 h in vitro treatment with 4 μM As2O3, 75 ± 18% of B cell chronic lymphocytic leukaemia (B-CLL) cells (n = 52) underwent apoptosis. It is important to note that B-CLL cells harboring a deletion of chromosome 17p13, which predisposes to fludarabine resistance and has been identified as an important negative predictor of clinical outcome, were more susceptible to As2O3 toxicity than cells lacking this aberration. Furthermore, unfavourable risk profiles such as unmutated IgVH status, high CD38 expression and prior treatment were associated with significantly higher sensitivity of B-CLL cells to As2O3. As2O3 also preferentially killed B-CLL cells compared to B cells from healthy age-matched controls. Molecular analysis revealed that basal superoxide dismutase activity was positively correlated with the pro-apoptotic activity of As2O3 pointing to a role of reactive oxygen species in cell death induction. The high activity of As2O3 in B-CLL cells from high-risk patients makes it a promising drug for high-risk and/or fludarabine-refractory B-CLL patients.

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Acknowledgements

We thank Nathalie Wacht and Elisabeth Hofstätter for the excellent technical assistance in the preparation of PBMCs, data collection and FISH analysis. We are grateful for the very good collaboration with the laboratory of Dr. Hans Georg Mustafa. Finally, we want to thank Rajam Csordas for the critical reading of the manuscript. The support of the FWF-project P16153 to I.T., the SFB programme F021 to R.G. and I.T., the research grant from EBEWE, Austria and FFF project no. 810222, the Verein zur Förderung für Klinische Malignom und Zytokinforschung (Innsbruck–Salzburg), GEN-AU project GOLD and the research grant from the Jubiläumsfond der Österreichischen Nationalbank project no. 12170 to R.G. are gratefully acknowledged.

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  1. Laboratory for Immunological and Molecular Cancer Research, IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectiology, Paracelsus Medical University Salzburg, Müllner Hauptstrasse 48, 5020, Salzburg, Austria

    Olaf Merkel, Christoph Heyder, Daniela Asslaber, Frank Hamacher, Inge Tinhofer, Claudia Holler, Markus Stöcher & Richard Greil

  2. Institute for Genomics and Bioinformatics, Graz University of Technology, Graz, Austria

    Andreas Prokesch, Christine Papak, Marcel Scheideler & Zlatko Trajanoski

  3. LIMCR, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020, Salzburg, Austria

    Olaf Merkel

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  1. Olaf Merkel
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Merkel, O., Heyder, C., Asslaber, D. et al. Arsenic trioxide induces apoptosis preferentially in B-CLL cells of patients with unfavourable prognostic factors including del17p13. J Mol Med 86, 541–552 (2008). https://doi.org/10.1007/s00109-008-0314-6

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  • DOI: https://doi.org/10.1007/s00109-008-0314-6

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