The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT-dependent apoptosis in diffuse large B-cell lymphoma

Blood. 2005 Jan 1;105(1):308-16. doi: 10.1182/blood-2004-01-0240. Epub 2004 Aug 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / genetics
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
  • Apoptosis*
  • Carrier Proteins
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / enzymology*
  • Lymphoma, Large B-Cell, Diffuse / pathology*
  • Mitochondria / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Protein Isoforms / metabolism
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • bcl-Associated Death Protein


  • BAD protein, human
  • Carrier Proteins
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • bcl-Associated Death Protein
  • Cyclic AMP
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Cyclic AMP-Dependent Protein Kinases
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, human
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases