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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 4, 2005 Accepted May 9, 2005 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* Division of Hematology/Oncology, Department of Medicine, Freiburg University Hospital, Freiburg, Germany Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, California, USA * Corresponding author; email: burger{at}mm11.ukl.uni-freiburg.de. Growth and survival of chronic lymphocytic leukemia (CLL) B cells are favored by interactions between CLL B cells and nontumoral accessory cells. CLL B cells express high levels of CXCR4 chemokine receptors (CD184) that direct leukemia cell chemotaxis. Marrow stromal cells or nurselike cells (NLC) constitutively secrete CXCL12, the ligand for CXCR4, thereby attract CLL B cells, and rescue CLL cells from apoptosis in a contact-dependent fashion. The CXCR4-CXCL12 axis therefore represents a potential therapeutic target in patients with this disease. We evaluated the most active CXCR4-specific antagonist T140, and its analogs TC14012, and TN14003 for their relative capacity to inhibit CXCL12 responses in CLL cells. T140, or its analogs, inhibited actin polymerization, leukemia-cell chemotaxis, and migration of CLL cells beneath marrow stromal cells. CXCL12-induced phosphorylation of p44/42 MAP kinase-(ERK1/2) and STAT3 phosphorylation was abolished by pre-treatment of CLL cells with such CXCR4 antagonists. TC14012 and TN14003 antagonized the anti-apoptotic effect of synthetic CXCL12 and stromal cell-mediated protection of CLL cells from spontaneous apoptosis. Furthermore, we found that culture of CLL cells on marrow stromal cells protected CLL cells from chemotherapy-induced apoptosis. Treatment with CXCR4 antagonists re-sensitized CLL cells cultured with stromal cells to fludarabine monophosphate-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-monophosphate induced apoptosis. As such, small molecular CXCR4 antagonits alone or in combination with other agents may have activity in the treatment of patients with this disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Enzler, A. P. Kater, W. Zhang, G. F. Widhopf II, H.-Y. Chuang, J. Lee, E. Avery, C. M. Croce, M. Karin, and T. J. Kipps Chronic lymphocytic leukemia of E{micro}-TCL1 transgenic mice undergoes rapid cell turnover that can be offset by extrinsic CD257 to accelerate disease progression Blood, November 12, 2009; 114(20): 4469 - 4476. [Abstract] [Full Text] [PDF] A. V. Kurtova, K. Balakrishnan, R. Chen, W. Ding, S. Schnabl, M. P. Quiroga, M. Sivina, W. G. Wierda, Z. Estrov, M. J. Keating, et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance Blood, November 12, 2009; 114(20): 4441 - 4450. [Abstract] [Full Text] [PDF] J. A. Burger, P. Ghia, A. Rosenwald, and F. Caligaris-Cappio The microenvironment in mature B-cell malignancies: a target for new treatment strategies Blood, October 15, 2009; 114(16): 3367 - 3375. [Abstract] [Full Text] [PDF] A. Vlad, P.-A. Deglesne, R. Letestu, S. Saint-Georges, N. 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[Abstract] [Full Text] [PDF] S. M. Eck, A. L. Cote, W. D. Winkelman, and C. E. Brinckerhoff CXCR4 and Matrix Metalloproteinase-1 Are Elevated in Breast Carcinoma-Associated Fibroblasts and in Normal Mammary Fibroblasts Exposed to Factors Secreted by Breast Cancer Cells Mol. Cancer Res., July 1, 2009; 7(7): 1033 - 1044. [Abstract] [Full Text] [PDF] M. Niedermeier, B. T. Hennessy, Z. A. Knight, M. Henneberg, J. Hu, A. V. Kurtova, W. G. Wierda, M. J. Keating, K. M. Shokat, and J. A. Burger Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach Blood, May 28, 2009; 113(22): 5549 - 5557. [Abstract] [Full Text] [PDF] A. V. Kurtova, A. T. Tamayo, R. J. Ford, and J. A. 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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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