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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1824-1830. Prepublished online as a Blood First Edition Paper on May 19, 2005; DOI 10.1182/blood-2004-12-4918. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-12-4918v1 106/5/1824    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 Burger, M. Articles by Burger, J. A. Search for Related Content PubMed PubMed Citation Articles by Burger, M. Articles by Burger, J. A. Related Collections Apoptosis Cell Adhesion and Motility Signal Transduction Chemokines, Cytokines, and Interleukins Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells Meike Burger, Tanja Hartmann, Myriam Krome, Justyna Rawluk, Hirokazu Tamamura, Nobutaka Fujii, Thomas J. Kipps, and Jan A. Burger From the Division of Hematology/Oncology, Department of Medicine, Freiburg University Hospital, Freiburg, Germany; the Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; and the Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, CA. Growth and survival of chronic lymphocytic leukemia (CLL) B cells are favored by interactions between CLL and nontumoral accessory cells. CLL cells express CXCR4 chemokine receptors that direct leukemia cell chemotaxis. Marrow stromal cells or nurselike cells constitutively secrete CXCL12, the ligand for CXCR4, thereby attracting and rescuing CLL B cells from apoptosis in a contact-dependent fashion. Therefore, the CXCR4-CXCL12 axis represents a potential therapeutic target in CLL. We evaluated the most active CXCR4-specific antagonists (T140, TC14012, TN14003) for their capacity to inhibit CXCL12 responses in CLL cells. T140, or its analogs, inhibited actin polymerization, chemotaxis, and migration of CLL cells beneath stromal cells. CXCL12-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) was abolished by CXCR4 antagonists. TC14012 and TN14003 antagonized the antiapoptotic effect of synthetic CXCL12 and stromal cell-mediated protection of CLL cells from spontaneous apoptosis. Furthermore, we found that stromal cells protected CLL cells from chemotherapy-induced apoptosis. Treatment with CXCR4 antagonists resensitized CLL cells cultured with stromal cells to fludarabine-induced apoptosis. These findings demonstrate that CXCR4 blocking agents effectively antagonize CXCL12-induced migratory and signaling responses and stromal protection of CLL cells from spontaneous or fludarabine-induced apoptosis. As such, small molecular CXCR4 antagonists may have activity in the treatment of patients with this disease. (Blood. 2005;106:1824-1830) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. B. Meads, L. A. Hazlehurst, and W. S. Dalton The Bone Marrow Microenvironment as a Tumor Sanctuary and Contributor to Drug Resistance Clin. Cancer Res., May 1, 2008; 14(9): 2519 - 2526. [Abstract] [Full Text] [PDF] T. Papayannopoulou and D. T. 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Cell Sci., November 15, 2007; 120(22): 4050 - 4059. [Abstract] [Full Text] [PDF] A. Burkle, M. Niedermeier, A. Schmitt-Graff, W. G. Wierda, M. J. Keating, and J. A. Burger Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia Blood, November 1, 2007; 110(9): 3316 - 3325. [Abstract] [Full Text] [PDF] Z. Zeng, I. J. Samudio, M. Munsell, J. An, Z. Huang, E. Estey, M. Andreeff, and M. Konopleva Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias Mol. Cancer Ther., December 1, 2006; 5(12): 3113 - 3121. [Abstract] [Full Text] [PDF] S. Mishra, B. Zhang, J. M. Cunnick, N. Heisterkamp, and J. Groffen Resistance to imatinib of bcr/abl p190 lymphoblastic leukemia cells. Cancer Res., May 15, 2006; 66(10): 5387 - 5393. [Abstract] [Full Text] [PDF] T. Kakinuma and S. T. Hwang Chemokines, chemokine receptors, and cancer metastasis J. Leukoc. Biol., April 1, 2006; 79(4): 639 - 651. [Abstract] [Full Text] [PDF] J. A. Burger and T. J. Kipps CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment Blood, March 1, 2006; 107(5): 1761 - 1767. [Abstract] [Full Text] [PDF]

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