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

摘要: 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 expression of PDE peripheral blood mononuclear cells (PBMC) healthy adults patients with CLL. We found a unique mRNA signature CLL: higher than normal PBMC PDE7B (increased ≈23-fold) PDE3B, 4D, 5A, 9A (each ≈30-fold). Increased CLL correlates 10-fold-higher protein results an increased contribution PDE7 total activity. Consistent level expression, inhibitors (BRL-50481, IR-202) dual PDE4/PDE7 inhibitor (IR-284) selectively increase compared or B cells. Apoptosis promoted by PDE4/7 is attenuated PKA inhibition, via mitochondrial-dependent process, associated accumulation down-regulation antiapoptotic survivin PDE7B. The inhibitor-promoted implicates as drug target Our findings identify illustrate utility broad analyses isoform human disease.