Targeting phosphodiesterase 7B and exchange protein directly activated by cAMP‐1 in chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B‐cells. We have shown that CLL is associated with increased mRNA expression of phosphodiesterase 7B (PDE7B), which catalyzes the hydrolysis of cAMP, and that PDE7 inhibitors promote apoptosis of CLL cells in a cAMP/protein kinase A‐dependent manner. In addition, we find that the expression of Exchange protein directly activated by cAMP (Epac), a downstream mediator of cAMP, is higher in CLL cells than in normal‐PBMC and B‐cells; its activation protects CLL cells from apoptosis. We investigated if the increase in PDE7B mRNA in CLL correlates with that of Epac‐1 and if targeted simultaneously would increase cAMP‐promoted apoptosis of CLL cells. We find that patients with CLL show a significant correlation between their fold‐increases in PDE7B and Epac‐1 mRNA (P<0.001, r=0.5395, n = 45). Inhibiting Epac‐1 or Epac‐1 signaling via siRNA (48 hr) or Rap‐1 inhibition (GGT1‐298, 5 μM, 48 hr), respectively, induced apoptosis in CLL cells and enhanced the pro‐apoptotic effect of PDE4/7 inhibition (IR‐284, 48 hr, 10nM). These data suggest that studies to define the regulation of PDE7B and Epac‐1 may provide insights into the pathophysiology of CLL and that decreasing the expression and function of Epac‐1 may be beneficial for treatment of CLL by increasing the pro‐apoptotic effects of PDE7 inhibitors. Supported by the Lymphoma and Leukemia Society and NIH.