title: Gene set enrichment analysis unveils the mechanism for the phosphodiesterase 4B control of glucocorticoid response in B-cell lymphoma.
abstract: OBJECTIVE
  Resistance to glucocorticoid (GC) is a significant problem in the clinical management of lymphoid malignancies. Addressing this issue via a mechanistic understanding of relevant signaling pathways is more likely to yield positive outcomes.
  
  
  METHODS
  We used gene set enrichment analysis (GSEA), multiple genetic models of gain and loss of function in B-cell lymphoma cell lines, in vitro and in vivo, and primary patient samples to characterize a novel relationship between the cyclic AMP/phosphodiesterase 4B (cAMP/PDE4B), AKT/mTOR activities, and GC responses.
  
  
  RESULTS
  Starting from the GSEA, we found that overexpression of the PDE4B in diffuse large B-cell lymphoma (DLBCL) impinge on the same genes/pathways that are abnormally active in GC-resistant tumors. We used genetically modified cell lines to show that PDE4B modulates cAMP inhibitory activities toward the AKT/mTOR pathway and defines GC resistance in DLBCL. In agreement with these data, pharmacologic inhibition of PDE4 in a xenograft model of human lymphoma unleashed cAMP effects, inhibited AKT, and restored GC sensitivity. Finally, we used primary DLBCL samples to confirm the clinical relevance and biomarker potential of AKT/mTOR regulation by PDE4B.
  
  
  CONCLUSIONS
  Together, these data mechanistically elucidated how cAMP modulates GC responses in lymphocytes, defined AKT as the principal transducer of the growth inhibitory effects of cAMP in B cells, and allowed the formulation of genomics-guided clinical trials that test the ability of PDE4 inhibitors to restore GC sensitivity and improve the outcome of patients with B-cell malignancies.
authors: Division of Hematology and Medical Oncology, Department of Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors: Sang-Woo
authors: SW
authors: Kim
authors: Deepak
authors: D
authors: Rai
authors: Ricardo C T
authors: RC
authors: Aguiar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone; D000242:Cyclic AMP; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human