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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6153-6160. Prepublished online as a Blood First Edition Paper on April 15, 2009; DOI 10.1182/blood-2009-02-206128. This Article Full Text Full Text (PDF) Supplemental Figures Additional Supplemental Figures All Versions of this Article: blood-2009-02-206128v1 113/24/6153    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 CrossRef Google Scholar Articles by Kim, S.-W. Articles by Aguiar, R. C. T. PubMed PubMed Citation Articles by Kim, S.-W. Articles by Aguiar, R. C. T. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL Sang-Woo Kim1, Deepak Rai1, Morgan R. McKeller1, and Ricardo C. T. Aguiar1 1 Division of Hematology and Medical Oncology, Department of Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio Identification of rational therapeutic targets is an important strategy to improve the cure rate of diffuse large B-cell lymphoma (DLBCL). We previously showed that inhibition of the phosphodiesterase 4B (PDE4B) unleashes cyclic-AMP (cAMP) inhibitory effects toward the PI3K/AKT pathway and induces apoptosis. These data raised important considerations as to which upstream regulators mediate cAMP inhibition of PI3K/AKT, and how identifying this signaling route could be translated into clinical initiatives. We found that in normal and malignant B cells, cAMP potently inhibit the phosphorylation and activity of the tyrosine kinase SYK. Using genetic models of gain- and loss-of-function, we demonstrated the essential role for PDE4B in controlling these effects in DLBCL. Furthermore, we used a constitutively active SYK mutant to confirm its central role in transducing cAMP effects to PI3K/AKT. Importantly, given SYK credentials as a therapeutic target in B-cell tumors, we explored the role of PDE4B in these responses. In multiple DLBCL models, we found that genetically, hence specifically, inhibiting PDE4B expression significantly improved the efficacy of SYK inhibitors. Our data defined a hitherto unknown role for cAMP in negatively regulating SYK and indicate that combined inhibition of PDE4B and SYK should be actively pursued. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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