Abstract
Cyclic nucleotide phosphodiesterase (PDE) isoforms can influence disease pathogenesis and be novel therapeutic targets. Because lower cAMP levels may contribute to the decreased apoptosis that occurs in chronic lymphocytic leukemia (CLL), we assessed the expression levels of PDE isoforms in peripheral blood mononuclear cells (PBMC) of healthy adults and patients with CLL. We found a unique PDE mRNA signature in CLL: higher levels than in normal PBMC of PDE7B (increased approximately 23-fold) and lower levels of PDE3B, 4D, 5A, and 9A mRNA (each decreased approximately 30-fold). Increased PDE7B mRNA in CLL correlates with a 10-fold-higher expression of PDE7B protein and results in an increased contribution of PDE7 to total PDE activity. Consistent with the higher level of PDE7B expression, inhibitors of PDE7 (BRL-50481, IR-202) and a dual PDE4/PDE7 inhibitor (IR-284) selectively increase apoptosis in CLL cells compared with normal PBMC or B cells. Apoptosis of CLL cells promoted by inhibitors of PDE7 and PDE4/7 is attenuated by PKA inhibition, occurs via a mitochondrial-dependent process, and is associated with increased cAMP accumulation and down-regulation of the antiapoptotic protein survivin and of PDE7B. The increase in PDE7B expression and PDE7 inhibitor-promoted apoptosis implicates PDE7B as a drug target in CLL. Our findings identify a unique PDE signature in CLL and illustrate the utility of broad analyses of PDE isoform expression in human disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / genetics
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism
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Apoptosis / immunology
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B-Lymphocytes / cytology
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B-Lymphocytes / enzymology*
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Cell Division / immunology
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Cells, Cultured
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 3 / genetics
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Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Cyclic Nucleotide Phosphodiesterases, Type 5 / genetics
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Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 7 / antagonists & inhibitors
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Cyclic Nucleotide Phosphodiesterases, Type 7 / genetics*
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Cyclic Nucleotide Phosphodiesterases, Type 7 / metabolism*
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Enzyme Activation / immunology
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Leukemic
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
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Leukemia, Lymphocytic, Chronic, B-Cell / physiopathology*
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Membrane Potential, Mitochondrial
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Phosphodiesterase 3 Inhibitors
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Phosphodiesterase Inhibitors / pharmacology
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RNA, Messenger / metabolism
Substances
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Phosphodiesterase 3 Inhibitors
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Phosphodiesterase Inhibitors
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RNA, Messenger
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 3
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Cyclic Nucleotide Phosphodiesterases, Type 7
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PDE3B protein, human
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PDE4D protein, human
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PDE9A protein, human
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Cyclic Nucleotide Phosphodiesterases, Type 5
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PDE5A protein, human