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Blood, 30 July 2009, Vol. 114, No. 5, pp. 1029-1037. Prepublished online as a Blood First Edition Paper on June 2, 2009; DOI 10.1182/blood-2009-03-212837. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2009-03-212837v1 114/5/1029    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 Google Scholar Articles by Quiroga, M. P. Articles by Burger, J. A. PubMed PubMed Citation Articles by Quiroga, M. P. Articles by Burger, J. A. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406 Maite P. Quiroga1, Kumudha Balakrishnan2, Antonina V. Kurtova1, Mariela Sivina1, Michael J. Keating1, William G. Wierda1, Varsha Gandhi1,2, and Jan A. Burger1 Departments of 1 Leukemia and 2 Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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] J. A. Burger and V. Gandhi The lymphatic tissue microenvironments in chronic lymphocytic leukemia: in vitro models and the significance of CD40-CD154 interactions Blood, September 17, 2009; 114(12): 2560 - 2561. [Full Text] [PDF]

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