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Blood, 1 January 2008, Vol. 111, No. 1, pp. 275-284. Prepublished online as a Blood First Edition Paper on August 29, 2007; DOI 10.1182/blood-2006-10-053884. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-10-053884v1 111/1/275    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Liu, Q. Articles by Byrd, J. C. Search for Related Content PubMed PubMed Citation Articles by Liu, Q. Articles by Byrd, J. C. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma Qing Liu1, Xiaobin Zhao1, Frank Frissora2, Yihui Ma3, Ramasamy Santhanam4, David Jarjoura5, Amy Lehman5, Danilo Perrotti4, Ching-Shih Chen3, James T. Dalton1, Natarajan Muthusamy2,4,6, and John C. Byrd14,6 1 Division of Pharmaceutics, College of Pharmacy, 2 Division of Hematology and Oncology, Department of Internal Medicine, 3 Division of Medicinal Chemistry, 4 Department of Molecular Virology, Immunology and Medical Genetics, 5 Center for Biostatistics, and 6 Department of Veterinary BioSciences, The Ohio State University, Columbus, OH FTY720 is an immunosuppressant developed to prevent organ transplant rejection. Recent studies indicate an additional role for FTY720 in inducing cell apoptosis. We demonstrate here that FTY720 mediates toxic effects in cell lines representing different B-cell malignancies and primary B cells from patients with chronic lymphocytic leukemia (CLL). In contrast to previous reports in T-cell lines, FTY720-induced toxicity in the Raji cell line and primary CLL B cells is independent of activation of caspases or poly(ADP-ribose) polymerase processing. Further, pancaspase inhibitor Z-VAD-fmk failed to rescue these cells from apoptosis mediated by FTY720. FTY720 induced down-regulation of Mcl-1 but not Bcl-2 in CLL B cells. Overexpression of Bcl-2 failed to protect transformed B cells from FTY720-induced apoptosis, suggesting a Bcl-2–independent mechanism. Interestingly, FTY720 induced protein phosphatase 2a (PP2a) activation and downstream dephosphorylation of ERK1/2, whereas okadaic acid at concentrations that inhibited the FTY720-induced PP2a activation also resulted in inhibition of FTY720-mediated apoptosis and restoration of baseline ERK1/2 phosphorylation in primary CLL cells, indicating a role for PP2a activation in FTY720-induced cytotoxicity. Further, FTY720 treatment resulted in significant prolonged survival in a xenograft severe combined immunodeficiency (SCID) mouse model of disseminated B-cell lymphoma/leukemia. These results provide the first evidence for the potential use of FTY720 as a therapeutic agent in a variety of B-cell malignancies, including CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. L. McConnell and B. E. Wadzinski Targeting Protein Serine/Threonine Phosphatases for Drug Development Mol. Pharmacol., June 1, 2009; 75(6): 1249 - 1261. [Abstract] [Full Text] [PDF] C. S. Bonder, W. Y. Sun, T. Matthews, C. Cassano, X. Li, H. S. Ramshaw, S. M. Pitson, A. F. Lopez, P. T. Coates, R. L. Proia, et al. Sphingosine kinase regulates the rate of endothelial progenitor cell differentiation Blood, February 26, 2009; 113(9): 2108 - 2117. [Abstract] [Full Text] [PDF] A. K. Ghosh, N. E. Kay, C. R. Secreto, and T. D. Shanafelt Curcumin Inhibits Prosurvival Pathways in Chronic Lymphocytic Leukemia B Cells and May Overcome Their Stromal Protection in Combination with EGCG Clin. Cancer Res., February 15, 2009; 15(4): 1250 - 1258. [Abstract] [Full Text] [PDF] V. R. Ruvolo, S. M. Kurinna, K. B. Karanjeet, T. F. Schuster, A. M. Martelli, J. A. McCubrey, and P. P. Ruvolo PKR Regulates B56{alpha}-mediated BCL2 Phosphatase Activity in Acute Lymphoblastic Leukemia-derived REH Cells J. Biol. Chem., December 19, 2008; 283(51): 35474 - 35485. [Abstract] [Full Text] [PDF]

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