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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1211-1219.
Prepublished online as a Blood First Edition Paper on October 3, 2006; DOI 10.1182/blood-2005-12-040972.
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Submitted December 5, 2005
Accepted August 28, 2006
Bcr-Abl signaling through the PI-3/S6 kinase pathway
inhibits nuclear translocation of the transcription
factor Bach2 which represses the anti-apoptotic factor
Hemeoxygenase-1
Chikashi Yoshida, Fumiko Yoshida, Daniel Sears, Stephen M Hart, Dai Ikebe, Akihiko Muto, Subham Basu, Kazuhiko Igarashi, and Junia V Melo*
Dept. of Haematology, Imperial College London, Hammersmith Hospital, London, UK
Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan
Dept of Biochemistry, Tohoku University School of Medicine, Sendai 980-8575, Japan
Cell Survival Signalling Laboratory, Cancer Research UK Molecular Oncology Unit, London, UK
Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK
* Corresponding author; email: j.melo{at}imperial.ac.uk.
The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the Bcr-Abl oncoprotein. We have previously reported that expression of the Bach2 transcription factor, which induces apoptosis in response to oxidative stress, is greatly reduced in CML cells. Since these cells are resistant to apoptosis, we tested whether Bach2 could be also regulated through post-translational mechanisms that promote inhibition of the apoptotic response to mutagenic stimuli in CML. We found that Bach2 is phosphorylated on S521 via the phosphatidylinositol-3/S6 kinase pathway, and substitution of this site to alanine leads to nuclear accumulation of the protein, indicating that this phosphorylation is important for its subcellular localization. Ectopic expression of the S521 mutant imparts greater impairment to CML cell growth
than the wild type factor. Furthermore, we showed that Bach2 transcriptionally represses heme oxygenase-1, an anti-apoptotic factor upregulated in CML. Since CML cells are known to produce high levels of intracellular reactive oxygen species, overexpression of heme oxygenase-1 resulting from inhibition of Bach2 activity may contribute to their genomic instability and leukemic phenotype.
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