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Chronic Myeloproliferative Neoplasias

Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway

Leukemia volume 23, pages 1432–1440 (2009)Cite this article

Abstract

Bcr-Abl causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells. In this study, inducible expression of Bcr-Abl in TonB.210 cells is associated with increased production of intracellular reactive oxygen species (ROS), which is thought to play a role in survival signaling when generated at specific levels. Elevated ROS in Bcr-Abl-expressing cells were found to activate PI3k/Akt pathway members such as Akt and GSK3β as well as downstream targets β-catenin and Mcl-1. The activation of these proteins was inhibited by the flavoprotein inhibitor diphenyleneiodonium, which is commonly used to inhibit NADPH oxidase (Nox). This indicated that increased ROS might be related to increased activity of one member of the Nox family. Knock-down experiments using siRNA suggest that Nox-4 is the main source of increased ROS following Bcr-Abl expression. We showed that Bcr-Abl-induced ROS could also increase survival pathway signaling through redox inhibition of PP1α, a serine threonine phosphatase that negatively regulates the PI3k/Akt pathway. Overall our results demonstrate that Bcr-Abl expression increases Nox-4-generated ROS, which in turn increases survival signaling through PI3k/Akt pathway by inhibition of PP1α, thus contributing to the high level of resistance to apoptosis seen in these Bcr-Abl-expressing cells.

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Acknowledgements

This work was supported by grants from Children Leukaemia Research Project, Irish Cancer Society and Health Research Board of Ireland.

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Author notes

  1. R Naughton and C Quiney: These authors contributed equally to this study.

Authors and Affiliations

  1. Biochemistry Department, Tumour Biology Laboratory, Bioscience Research Institute, University College, Cork, Ireland

    R Naughton, C Quiney, S D Turner & T G Cotter

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  1. R Naughton
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  2. C Quiney
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  3. S D Turner
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  4. T G Cotter
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Correspondence to T G Cotter.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Naughton, R., Quiney, C., Turner, S. et al. Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway. Leukemia 23, 1432–1440 (2009). https://doi.org/10.1038/leu.2009.49

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