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Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia.
Proc Natl Acad Sci U S A. 2008 Dec 09; 105(49):19532-7.PN

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.

Authors+Show Affiliations

Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093-0636, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19033455

Citation

Zhang, Lingzhi, et al. "Cyclic Nucleotide Phosphodiesterase Profiling Reveals Increased Expression of Phosphodiesterase 7B in Chronic Lymphocytic Leukemia." Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 49, 2008, pp. 19532-7.
Zhang L, Murray F, Zahno A, et al. Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2008;105(49):19532-7.
Zhang, L., Murray, F., Zahno, A., Kanter, J. R., Chou, D., Suda, R., Fenlon, M., Rassenti, L., Cottam, H., Kipps, T. J., & Insel, P. A. (2008). Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America, 105(49), 19532-7. https://doi.org/10.1073/pnas.0806152105
Zhang L, et al. Cyclic Nucleotide Phosphodiesterase Profiling Reveals Increased Expression of Phosphodiesterase 7B in Chronic Lymphocytic Leukemia. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19532-7. PubMed PMID: 19033455.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia. AU - Zhang,Lingzhi, AU - Murray,Fiona, AU - Zahno,Anja, AU - Kanter,Joan R, AU - Chou,Daisy, AU - Suda,Ryan, AU - Fenlon,Michael, AU - Rassenti,Laura, AU - Cottam,Howard, AU - Kipps,Thomas J, AU - Insel,Paul A, Y1 - 2008/11/25/ PY - 2008/11/27/pubmed PY - 2009/1/31/medline PY - 2008/11/27/entrez SP - 19532 EP - 7 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 105 IS - 49 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/19033455/Cyclic_nucleotide_phosphodiesterase_profiling_reveals_increased_expression_of_phosphodiesterase_7B_in_chronic_lymphocytic_leukemia_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=19033455 DB - PRIME DP - Unbound Medicine ER -