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

[Guest guest]

Cyclic nucleotide phosphodiesterase profiling reveals increased expression of

phosphodiesterase 7B in chronic lymphocytic leukemia

1.. Lingzhi Zhanga,1,

2.. Fiona Murraya,1,

3.. Anja Zahnoa,

4.. Joan R. Kantera,

5.. Daisy Choua,

6.. Sudaa,

7.. Fenlonb,c,

8.. Rassentib,c,

9.. Cottamb,c,

10.. J. Kippsb,c, and

11.. A. Insela,b,c,2

+Author Affiliations

1.. Departments of aPharmacology and

2.. bMedicine and

3.. cs Cancer Center, University of California at San Diego, La Jolla, CA

92093

1.. Edited by ph A. Beavo, University of Washington School of Medicine,

Seattle, WA, and approved October 20, 2008

2.. ?1L.Z. and F.M. contributed equally to this work. (received for review

June 25, 2008)

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 ?23-fold) and lower levels of PDE3B, 4D, 5A, and 9A mRNA (each

decreased ?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.

a.. 2To whom correspondence should be addressed at:

Department of Pharmacology, University of California at San Diego, BSB 3073,

9500 Gilman Drive, La Jolla, CA 92093-0636.

E-mail: pinsel@...