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Increased IκB kinase activity is associated with activated NF-κB in acute myeloid blasts

Leukemia volume 16, pages 2062–2071 (2002)Cite this article

Abstract

NF-κB/Rel transcription factors are modulators of immune and inflammatory processes and are also involved in malignancy. Phosphorylation of the IκB inhibitors by the IκB kinase (IKK) complex leads to their proteasomal degradation, resulting in activated NF-κB. Here, we investigated the activation status of NF-κB and the IKK complex in acute myeloid leukemia (AML). Gelshift assays revealed an increased level of activated nuclear NF-κB in myeloid blasts. Both bone marrow and peripheral blood blasts from AML patients showed enhanced IKK activity relative to controls, whereas the IKK protein concentrations were comparable. In addition, an increased level of IκB-α was detected in AML blast cells, although this appeared to be insufficient to block nuclear translocation of NF-κB, also confirmed by immunofluorescence. In subtype M4 and M5 AML cells a more extensive NF-κB activation and higher IKK activity was found than in M1/M2 specimens. Isolated AML blasts cultured ex vivoresponded to external stimulation (TNF, LPS) by further IKK activation, IκB degradation and NF-κB activation. Preincubation with the proteasome inhibitor PSI inhibited the NF-κB system in isolated AML blasts. This study established for the first time a dysregulation of IKK signaling in AML leading to increased NF-κB activity suggesting potential therapeutic avenues.

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Acknowledgements

Special thanks to Tamara Eisele for excellent technical assistance as well as to Margit Obst, Marion Barchfeld and Doris Schmidbauer from the hematological laboratory of the Institute of Clinical Chemistry and Pathobiochemistry for their support during this project. We also thank Michael Henning from the Institute for Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universität München, for help with the statistical analyses. This work was supported by the Deutsche Forschungsgemeinschaft (Br 1026/3-3) and by the Medical Faculty of the Technische Universität München (H 50-98).

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Author notes

  1. B Baumgartner and M Weber: The first two authors contributed equally to this work

Authors and Affiliations

  1. Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität, München, Germany

    B Baumgartner, M Weber, M Quirling, C Fischer, S Page, D Neumeier & K Brand

  2. Department of Hematology/Oncology, Klinikum rechts der Isar, Technische Universität, München, Germany

    C von Schilling

  3. Institute of Clinical Chemistry, Klinikum Groβhadern, Ludwig-Maximillians-Universität, München, Germany

    M Adam

  4. Department of Hematology/Oncology, Klinikum Groβhadern, Ludwig-Maximilians-Universität, München, Germany

    C Schmid

  5. Department of Hematology/Oncology, Akademisches Lehrkrankenhaus München-Schwabing, Germany

    C Waterhouse

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Correspondence to K Brand.

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In memory of Maria Brand-Bartsch who died from AML.

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Baumgartner, B., Weber, M., Quirling, M. et al. Increased IκB kinase activity is associated with activated NF-κB in acute myeloid blasts. Leukemia 16, 2062–2071 (2002). https://doi.org/10.1038/sj.leu.2402641

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