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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2484-2494
Type 4 Cyclic Adenosine Monophosphate Phosphodiesterase as a
Therapeutic Target in Chronic Lymphocytic Leukemia
Doo Ho Kim and
Adam Lerner
From the Department of Medicine, Section of Hematology and Oncology,
Boston Medical Center, Boston, MA.
Theophylline, a drug known to inhibit several classes of adenosine
3 5 cyclic monophosphate (cAMP) phosphodiesterases (PDEs), induces apoptosis in chronic lymphocytic leukemia (CLL) cells. Because
the PDE target for theophylline in CLL remains unknown, we examined the
ability of isoform-specific PDE inhibitors to increase cAMP levels and
induce apoptosis in primary CLL cells. Reverse transcriptase-polymerase
chain reaction of purified CLL cDNA amplified transcripts for PDE1B, 4A
and 4B. The type 4 PDE inhibitor rolipram but not the type 1 inhibitor
vinpocetine increased CLL cAMP levels. Rolipram-inhibitable (type 4)
but not calcium-calmodulin augmented (type 1) PDE enzyme activity was
detected in CLL samples. In samples from 13 of 14 CLL patients,
rolipram induced apoptosis in a dose-dependent fashion over a 48-hour
period. Interleukin-2 (IL-2)-cultured whole mononuclear cells (WMC)
and anti-Ig stimulated CD19+ B cells were resistant to
the induction of apoptosis by rolipram while unstimulated
CD19+ B cells, which had a high basal apoptotic rate,
were more sensitive. Rolipram stimulated elevations in cAMP levels in
all four of these cell populations, suggesting that they differed in
sensitivity to cAMP-induced apoptosis. Consistent with this hypothesis,
incubation with the cell permeable cAMP analog dibutyryl-cAMP induced
apoptosis in CLL cells and unstimulated B cells but not in
IL-2-cultured WMC or anti-Ig stimulated B cells. These data identify
PDE4 as a family of enzymes whose inhibition induces apoptosis in CLL cells.
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