Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia

Lingzhi Zhang, Fiona Murray, Anja Zahno, Joan R. Kanter, Daisy Chou, Ryan Suda, Michael Fenlon, Laura Rassenti, Howard Cottam, Thomas J. Kipps, Paul A. Insel*

*Corresponding author for this work

Research output: Contribution to journalArticle

67 Citations (Scopus)

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 approximate to 23-fold) and lower levels of PDE3B, 4D, 5A, and 9A mRNA (each decreased approximate to 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.

Original languageEnglish
Pages (from-to)19532-19537
Number of pages6
JournalPNAS
Volume105
Issue number49
Early online date25 Nov 2008
DOIs
Publication statusPublished - 9 Dec 2008

Keywords

  • survivin
  • gene-expression
  • apoptosis
  • therapeutic targets
  • AMP
  • cells
  • human B-Lymphocytes
  • B cell
  • cAMP
  • camp-specific phosphodiesterase
  • pathway
  • theophylline
  • inhibitor-induced apoptosis
  • protein-kinase

Cite this

Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia. / Zhang, Lingzhi; Murray, Fiona; Zahno, Anja; Kanter, Joan R.; Chou, Daisy; Suda, Ryan; Fenlon, Michael; Rassenti, Laura; Cottam, Howard; Kipps, Thomas J.; Insel, Paul A.

In: PNAS, Vol. 105, No. 49, 09.12.2008, p. 19532-19537.

Research output: Contribution to journalArticle

Zhang, L, Murray, F, Zahno, A, Kanter, JR, Chou, D, Suda, R, Fenlon, M, Rassenti, L, Cottam, H, Kipps, TJ & Insel, PA 2008, 'Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia', PNAS, vol. 105, no. 49, pp. 19532-19537. https://doi.org/10.1073/pnas.0806152105
Zhang, Lingzhi ; Murray, Fiona ; Zahno, Anja ; Kanter, Joan R. ; Chou, Daisy ; Suda, Ryan ; Fenlon, Michael ; Rassenti, Laura ; Cottam, Howard ; Kipps, Thomas J. ; Insel, Paul A. / Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia. In: PNAS. 2008 ; Vol. 105, No. 49. pp. 19532-19537.
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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.

PY - 2008/12/9

Y1 - 2008/12/9

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 approximate to 23-fold) and lower levels of PDE3B, 4D, 5A, and 9A mRNA (each decreased approximate to 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.

AB - 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 approximate to 23-fold) and lower levels of PDE3B, 4D, 5A, and 9A mRNA (each decreased approximate to 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.

KW - survivin

KW - gene-expression

KW - apoptosis

KW - therapeutic targets

KW - AMP

KW - cells

KW - human B-Lymphocytes

KW - B cell

KW - cAMP

KW - camp-specific phosphodiesterase

KW - pathway

KW - theophylline

KW - inhibitor-induced apoptosis

KW - protein-kinase

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DO - 10.1073/pnas.0806152105

M3 - Article

VL - 105

SP - 19532

EP - 19537

JO - PNAS

JF - PNAS

SN - 0027-8424

IS - 49

ER -