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, Ricardo C.T. Aguiar

Research output: Contribution to journalArticlepeer-review

129 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)308-316
Number of pages9
Issue number1
StatePublished - Jan 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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