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Chronic Lymphocytic Leukemia and B and T Cells Differ in Their Response to Cyclic Nucleotide Phosphodiesterase Inhibitors¹

John A. Meyers^*,, Derrick W. Su^* and Adam Lerner^2,*,

^* Evans Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, MA 02118; and Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118

Phosphodiesterase (PDE)4 inhibitors, which activate cAMP signaling by reducing cAMP catabolism, are known to induce apoptosis in B lineage chronic lymphocytic leukemia (CLL) cells but not normal human T cells. The explanation for such differential sensitivity remains unknown. In this study, we report studies contrasting the response to PDE4 inhibitor treatment in CLL cells and normal human T and B cells. Affymetrix gene chip analysis in the three cell populations following treatment with the PDE4 inhibitor rolipram identified a set of up-regulated transcripts with unusually high fold changes in the CLL samples, several of which are likely part of compensatory negative feedback loops. The high fold changes were due to low basal transcript levels in CLL cells, suggesting that cAMP-mediated signaling may be unusually tightly regulated in this cell type. Rolipram treatment augmented cAMP levels and induced ATF-1/CREB serine 63/133 phosphorylation in both B lineage cell types but not T cells. As treatment with the broad-spectrum PDE inhibitor 3-isobutyl-1-methylxanthine induced T cell CREB phosphorylation, we tested a series of family-specific PDE inhibitors for their ability to mimic 3-isobutyl-1-methylxanthine-induced ATF-1/CREB phosphorylation. Whereas PDE3 inhibitors alone had no effect, the combination of PDE3 and PDE4 inhibitors induced ATF-1/CREB serine 63/133 phosphorylation in T cells. Consistent with this observation, PDE3B transcript and protein levels were low in CLL cells but easily detectable in T cells. Combined PDE3/4 inhibition did not induce T cell apoptosis, suggesting that cAMP-mediated signal transduction that leads to robust ATF-1/CREB serine 63/133 phosphorylation is not sufficient to induce apoptosis in this lymphoid lineage.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded in part by National Cancer Institute Grant CA106705 and by a National Heart, Lung, and Blood Institute-supported Boston University School of Medicine Hematology Training Grant (HL007501; to J.A.M.).

² Address correspondence and reprint requests to Dr. Adam Lerner, Hematology/Oncology Section, Boston Medical Center, EBRC 420, 650 Albany Street, Boston, MA 02118. E-mail address: lernwara{at}bu.edu

³ Abbreviations used in this paper: PDE, phosphodiesterase; ATF, activating transcription factor; CLL, chronic lymphocytic leukemia; CREM, cAMP response element modulator; IBMX, 3-isobutyl-1-methylxanthine; PCA, principal component analysis; PKA, protein kinase A; WBC, white blood cell; GPCR, G protein-coupled receptor; EPAC, exchange protein activated by cAMP; AC, adenylate cyclase; BAD, Bcl2-antagonist of death.

⁴ The online version of this article contains supplemental material.