|
|
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.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
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. T. Aguiar
From the Department of Medical Oncology and the Department of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; the Institute for Cancer Genetics, Columbia University, New York, NY; and Plexxikon, Berkeley, CA.
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 DLBCL and found that the phosphodiesterase PDE4B was overexpressed in fatal/refractory tumors. Phosphodiesterase 4B (PDE4B) inactivates the second messenger cyclic adenosine 3',5' monophosphate (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 the enzyme's 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, protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), but associated with inhibition of the phosphatidylinositol 3-kinase (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. (Blood. 2005;105:308-316)
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
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]
|
|
|
|
|
