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Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells

Oncogene volume 26, pages 7904–7908 (2007)Cite this article

Abstract

The signaling mechanisms responsible for BCR/ABL-induced regulation of Mcl-1 expression in chronic myelogenous leukemia (CML) cells remain unclear. In this study, we show that BCR/ABL could upregulate sphingosine kinase-1 (SPK1) expression via multiple signal pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) and Janus kinase 2 (JAK2), leading to increase cellular SPK1 activity in CML cells. Retrovirus-mediated overexpression of bcr-abl gene in NIH-3T3, Ba/F3 and HL-60 cells results in upregulation and increased cellular activity of SPK1, whereas treatment of CML cells with specific inhibitors of the BCR/ABL, PI3K, MAPK and JAK2 pathways decreases BCR/ABL-induced SPK1 expression and cellular activity. BCR/ABL also induces upregulation of Mcl-1 expression in CML cells. Inhibition of SPK1 by adenovirus-mediated transfer of small interfering RNA or N,N-dimethylsphingosine reduced expression of Mcl-1 in CML cells. Our data indicated that BCR/ABL induces SPK1 expression and increases its cellular activity, leading to upregulation of Mcl-1 in CML cells. SPK1 silencing enhances the STI571-induced apoptosis of CML cell lines. It is suggested that SPK1 may be a potential therapeutic target in CML.

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Acknowledgements

This work was supported by Chinese National Basic Research and Development Grants ‘973’ (nos. 2004CB518801 and 2002CB713804) and Chinese National Science Foundations.

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  1. Q-F Li and W-R Huang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, PR China

    Q-F Li, H-F Duan, H Wang, C-T Wu & L-S Wang

  2. Department of Hematology, PLA General Hospital, Beijing, PR China

    W-R Huang

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  1. Q-F Li
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Correspondence to L-S Wang.

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Li, QF., Huang, WR., Duan, HF. et al. Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells. Oncogene 26, 7904–7908 (2007). https://doi.org/10.1038/sj.onc.1210587

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