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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-01-0189. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-01-0189v1 101/1/278    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 Decker, T. Articles by Peschel, C. Search for Related Content PubMed PubMed Citation Articles by Decker, T. Articles by Peschel, C. Related Collections Neoplasia Cell Cycle Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 January 2003, Vol. 101, No. 1, pp. 278-285 NEOPLASIA Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin Thomas Decker, Susanne Hipp, Ingo Ringshausen, Christian Bogner, Madlene Oelsner, Folker Schneller, and Christian Peschel From the 3rd Department of Medicine, Technical University of Munich, Munich, Germany. In B-cell chronic lymphocytic leukemia (B-CLL), malignant cells seem to be arrested in the G0/early G1 phase of the cell cycle, and defective apoptosis might be involved in disease progression. However, increasing evidence exists that B-CLL is more than a disease consisting of slowly accumulating resting B cells: a proliferating pool of cells has been described in lymph nodes and bone marrow and might feed the accumulating pool in the blood. Rapamycin has been reported to inhibit cell cycle progression in a variety of cell types, including human B cells, and has shown activity against a broad range of human tumor cell lines. Therefore, we investigated the ability of rapamycin to block cell cycle progression in proliferating B-CLL cells. We have recently demonstrated that stimulation with CpG-oligonucleotides and interleukin-2 provides a valuable model for studying cell cycle regulation in malignant B cells. In our present study, we demonstrated that rapamycin induced cell cycle arrest in proliferating B-CLL cells and inhibited phosphorylation of p70s6 kinase (p70s6k). In contrast to previous reports on nonmalignant B cells, the expression of the cell cycle inhibitor p27 was not changed in rapamycin-treated leukemic cells. Treatment with rapamycin prevented retinoblastoma protein (RB) phosphorylation in B-CLL cells without affecting the expression of cyclin D2, but cyclin D3 was no longer detectable in rapamycin-treated B-CLL cells. In addition, rapamycin treatment inhibited cyclin-dependent kinase 2 activity by preventing up-regulation of cyclin E and cyclin A. Interestingly, survivin, which is expressed in the proliferation centers of B-CLL patients in vivo, is not up-regulated in rapamycin-treated cells. Therefore, rapamycin interferes with the expression of many critical molecules for cell cycle regulation in cycling B-CLL cells. We conclude from our study that rapamycin might be an attractive substance for therapy for B-CLL patients by inducing a G1 arrest in proliferating tumor cells. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Ferri, A. Granata, C. Pirola, F. Torti, P. J. Pfister, R. Dorent, and A. Corsini Fluvastatin Synergistically Improves the Antiproliferative Effect of Everolimus on Rat Smooth Muscle Cells by Altering p27Kip1/Cyclin E Expression Mol. Pharmacol., July 1, 2008; 74(1): 144 - 153. [Abstract] [Full Text] [PDF] C. Gridelli, P. Maione, and A. Rossi The Potential Role of mTOR Inhibitors in Non-Small Cell Lung Cancer Oncologist, February 1, 2008; 13(2): 139 - 147. [Abstract] [Full Text] [PDF] K. S. Gotze, D. Hoffmann, H. M. Schatzl, C. Peschel, F. Fend, and T. 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