SEARCH:   Advanced

Blood, 1 January 2005, Vol. 105, No. 1, pp. 308-316. Prepublished online as a Blood First Edition Paper on August 26, 2004; DOI 10.1182/blood-2004-01-0240. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: 2004-01-0240v1 105/1/308    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 Smith, P. G Articles by Aguiar, R. C Search for Related Content PubMed PubMed Citation Articles by Smith, P. G Articles by Aguiar, R. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 20, 2004 Accepted August 11, 2004 The phosphodiesterase PDE4B limits cAMP associated, PI3K-AKT dependent, apoptosis in diffuse large B-cell lymphoma Peter G Smith, Fengfei Wang, Kathryn N Wilkinson, Kerry J Savage, Ulf Klein, Donna S Neuberg, Gideon Bollag, Margaret A Shipp, and Ricardo C Aguiar* Dept. of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Institute for Cancer Genetics, Columbia University, New York, NY, USA Dept. of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Plexxikon Inc., Berkeley, CA, USA * Corresponding author; email: Ricardo_Aguiar{at}dfci.harvard.edu. Diffuse Large B-cell Lymphoma (DLBCL) is a common and often fatal malignancy. Advances in the treatment of this disease will require the identification of novel therapeutic targets. We previously defined an expression signature of outcome in DLCBL and found that the phosphodiesterase PDE4B was overexpressed in fatal/refractory tumors. PDE4B inactivates the second messenger cAMP and abrogates its inhibitory effects in B-lymphocytes. Hence, DLBCLs that express high PDE4B levels may be resistant to cAMP-induced apoptosis, contributing to their less favorable outcome. Herein, we confirmed the risk-related expression of PDE4B in an independent series of primary DLBCLs and defined this enzyme role in modulating cAMP-induced apoptosis in parental DLBCL cell lines or those reconstituted with wild-type or mutant PDE4B. The cAMP-mediated apoptosis of DLBCLs was largely independent of the previously described cAMP effectors, PKA and EPAC, but associated with inhibition of the PI3K/AKT pathway. The central role of AKT in this process was confirmed by expressing constitutively active mutants of this kinase in DLBCL cells. Our findings highlight the important role of cAMP signaling in DLBCL and suggest that clinically relevant PDE4 and PI3K/AKT inhibitors might be useful in the treatment of DLBCL and additional B-lymphoid malignancies with increased PDE4B expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S.-W. Kim, D. Rai, M. R. McKeller, and R. C. T. Aguiar Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL Blood, June 11, 2009; 113(24): 6153 - 6160. [Abstract] [Full Text] [PDF] S. Kumar, S. Kostin, J.-P. Flacke, H. P. Reusch, and Y. Ladilov Soluble Adenylyl Cyclase Controls Mitochondria-dependent Apoptosis in Coronary Endothelial Cells J. Biol. Chem., May 29, 2009; 284(22): 14760 - 14768. [Abstract] [Full Text] [PDF] K. Hong, L. Lou, S. Gupta, F. Ribeiro-Neto, and D. L. Altschuler A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation J. Biol. Chem., August 22, 2008; 283(34): 23129 - 23138. [Abstract] [Full Text] [PDF] P. Juszczynski, J. Ouyang, S. Monti, S. J. Rodig, K. Takeyama, J. Abramson, W. Chen, J. L. Kutok, G. A. Rabinovich, and M. A. Shipp The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma PNAS, August 7, 2007; 104(32): 13134 - 13139. [Abstract] [Full Text] [PDF] K. Omori and J. Kotera Overview of PDEs and Their Regulation Circ. Res., February 16, 2007; 100(3): 309 - 327. [Abstract] [Full Text] [PDF] M.-A. Lyu, L. H. Cheung, W. N. Hittelman, J. W. Marks, R. C.T. Aguiar, and M. G. Rosenblum The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA Mol. Cancer Ther., February 1, 2007; 6(2): 460 - 470. [Abstract] [Full Text] [PDF] M. A. Shipp Molecular Signatures Define New Rational Treatment Targets in Large B-Cell Lymphomas Hematology, January 1, 2007; 2007(1): 265 - 269. [Abstract] [Full Text] [PDF] S. Uddin, A. R. Hussain, A. K. Siraj, P. S. Manogaran, N. A. Al-Jomah, A. Moorji, V. Atizado, F. Al-Dayel, A. Belgaumi, H. El-Solh, et al. Role of phosphatidylinositol 3'-kinase/AKT pathway in diffuse large B-cell lymphoma survival Blood, December 15, 2006; 108(13): 4178 - 4186. [Abstract] [Full Text] [PDF] J. Zhang, T. N. Bui, J. Xiang, and A. Lin Cyclic AMP Inhibits p38 Activation via CREB-Induced Dynein Light Chain Mol. Cell. Biol., February 15, 2006; 26(4): 1223 - 1234. [Abstract] [Full Text] [PDF] R. Gros, Q. Ding, J. Chorazyczewski, J. Andrews, J. G. Pickering, R. A. Hegele, and R. D. Feldman The Impact of Blunted beta-Adrenergic Responsiveness on Growth Regulatory Pathways in Hypertension Mol. Pharmacol., January 1, 2006; 69(1): 317 - 327. [Abstract] [Full Text] [PDF] A. Hachem and R. B. Gartenhaus Oncogenes as molecular targets in lymphoma Blood, September 15, 2005; 106(6): 1911 - 1923. [Full Text] [PDF] I. S. Lossos Molecular Pathogenesis of Diffuse Large B-Cell Lymphoma J. Clin. Oncol., September 10, 2005; 23(26): 6351 - 6357. [Abstract] [Full Text] [PDF] J. S. Abramson and M. A. Shipp Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach Blood, August 15, 2005; 106(4): 1164 - 1174. [Abstract] [Full Text] [PDF] S. N. Kip, L. W. Hunter, Q. Ren, P. C. Harris, S. Somlo, V. E. Torres, G. C. Sieck, and Q. Qian [Ca2+]i Reduction Increases Cellular Proliferation and Apoptosis in Vascular Smooth Muscle Cells: Relevance to the ADPKD Phenotype Circ. Res., April 29, 2005; 96(8): 873 - 880. [Abstract] [Full Text] [PDF] S. Monti, K. J. Savage, J. L. Kutok, F. Feuerhake, P. Kurtin, M. Mihm, B. Wu, L. Pasqualucci, D. Neuberg, R. C. T. Aguiar, et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response Blood, March 1, 2005; 105(5): 1851 - 1861. [Abstract] [Full Text] [PDF]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020