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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1808-1816. Prepublished online as a Blood First Edition Paper on May 12, 2005; DOI 10.1182/blood-2004-12-4832. This Article Full Text (PDF) All Versions of this Article: 2004-12-4832v1 106/5/1808    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeScolan, E. Articles by Moreau-Gachelin, F. Search for Related Content PubMed PubMed Citation Articles by LeScolan, E. Articles by Moreau-Gachelin, F. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 21, 2004 Accepted May 2, 2005 Overexpression of sphingosine kinase 1 is an oncogenic event in erythroleukemic progression Erwan LeScolan, Dimitri Pchejetski, Yoshiko Banno, Nicole Denis, Patrick Mayeux, William Vainchenker, Thierry Levade, and Francoise Moreau-Gachelin* Inserm U528 - Institut Curie, Paris, France Inserm U466 - Institut Louis Bugnard - Hopital Rangueil, Toulouse, France Department of Cell Signaling, Gifu University School of Medicine, Gifu, Japan Institut Cochin, Inserm, Paris, France Inserm U362 - Institut Gustave Roussy, Villejuif, France * Corresponding author; email: framoreau{at}curie.fr. The erythroleukemia developed by spi-1/PU.1-transgenic mice is a model of multistage oncogenic process. Isolation of tumor cells representing discrete stages of leukemic progression enables to dissect some of the critical events required for malignant transformation. To elucidate the molecular mechanisms of multistage leukemogenesis, we developed a microarray transcriptome analysis of non tumorigenic (HS1) and tumorigenic (HS2) proerythroblasts from spi-1-transgenic mice. The data show that transcriptional up-regulation of the sphingosine kinase gene (SPHK1) is a recurrent event associated to the tumorigenic phenotype of these transgenic proerythroblasts. SPHK1 is an enzyme of the metabolism of sphingolipids which are essential in several biological processes including cell proliferation and apoptosis. HS1 erythroleukemic cells engineered to overexpress the SPHK1 protein exhibited growth proliferative advantage, increased clonogenicity and resistance to apoptosis in reduced serum level by a mechanism involving activation of the ERK1/2 and PI3K/AKT pathways. In addition, SPHK1-overexpressing HS1 cells acquired tumorigenicity when engrafted in vivo. Finally, enforced expression of a dominant-negative mutant of SPHK1 in HS2 tumorigenic cells or treatment with a pharmacological inhibitor reduced both cell growth and apoptosis resistance. Altogether, these data suggest that overexpression of the sphingosine kinase may represent an oncogenic event during the multistep progression of an erythroleukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Kapitonov, J. C. Allegood, C. Mitchell, N. C. Hait, J. A. Almenara, J. K. Adams, R. E. Zipkin, P. Dent, T. Kordula, S. Milstien, et al. Targeting Sphingosine Kinase 1 Inhibits Akt Signaling, Induces Apoptosis, and Suppresses Growth of Human Glioblastoma Cells and Xenografts Cancer Res., September 1, 2009; 69(17): 6915 - 6923. [Abstract] [Full Text] [PDF] W. Li, C.-P. Yu, J.-t. Xia, L. Zhang, G.-X. Weng, H.-q. Zheng, Q.-l. Kong, L.-j. Hu, M.-S. Zeng, Y.-x. Zeng, et al. Sphingosine Kinase 1 Is Associated with Gastric Cancer Progression and Poor Survival of Patients Clin. Cancer Res., February 15, 2009; 15(4): 1393 - 1399. [Abstract] [Full Text] [PDF] J. Li, H.-Y. Guan, L.-Y. Gong, L.-B. Song, N. Zhang, J. Wu, J. Yuan, Y.-J. Zheng, Z.-S. Huang, and M. Li Clinical Significance of Sphingosine Kinase-1 Expression in Human Astrocytomas Progression and Overall Patient Survival Clin. Cancer Res., November 1, 2008; 14(21): 6996 - 7003. [Abstract] [Full Text] [PDF] P. Rimmele, O. Kosmider, P. Mayeux, F. Moreau-Gachelin, and C. Guillouf Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation Blood, April 1, 2007; 109(7): 3007 - 3014. [Abstract] [Full Text] [PDF]

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