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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.
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Submitted October 24, 2006
Accepted July 18, 2007
FTY720 demonstrates promising pre-clinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma
Qing Liu, Xiaobin Zhao, Frank Frissora, Yihui Ma, Ramasamy Santhanam, David Jarjoura, Amy Lehman, Danilo Perrotti, Ching-Shih Chen, James T Dalton, Natarajan Muthusamy, and John C Byrd*
Div. of Pharmaceutics, College of Pharmacy, Div. of Hematology & Oncology, Dept. of Internal Medicine, The Ohio State University, Columbus, OH
Div. of Medicinal Chemistry, Molecular Virology, Immunology, & Medical Genetics, Dept of Biostatistics & Veterinary BioSciences, The Ohio State University, Columbus, OH
* Corresponding author; email: john.byrd{at}osumc.edu.
FTY720 is an immunosuppressant developed to prevent organ transplant rejection. Recent studies indicate 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 chronic lymphocytic leukemia (CLL) patients. In contrast to previous reports in T cell lines, FTY720 induced toxicity in Raji cell line and primary CLL B cells is independent of activation of caspases or poly-ADP ribose polymerase processing. Further, pan-caspase 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 and over-expression of Bcl-2 failed to protect transformed B-cells from FTY720 induced apoptosis. Interestingly, FTY720 induced protein phosphatase 2a (PP2a) activation and down-stream de-phosphorylation 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 CLL cells, indicating a role for PP2a activation in FTY720 induced cytotoxicity. Further, FTY720 treatment resulted in significant prolonged survival in a xenograft SCID mouse model of systemic B cell lymphoma/leukemia. These results provide first evidence for the potential use of FTY720 as a therapeutic agent in a variety of B-cell malignancies including CLL.
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