DEFECTIVE NITROVASODILATOR-STIMULATED PROTEIN-PHOSPHORYLATION AND CALCIUM REGULATION IN CGMP-DEPENDENT PROTEIN KINASE-DEFICIENT HUMAN PLATELETS OF CHRONIC MYELOCYTIC-LEUKEMIA

The presence and functional role of the cyclic nucleotide signal trans duction system was investigated in platelets from patients with myelop roliferative disorders. Platelets from certain patients with chronic m yelocytic leukemia showed decreased expression of cGMP-dependent prote in kinase, and platelets from two such patients were studied in some d etail. These platelets had very little if any cGMP-dependent protein k inase but a normal level of cAMP-dependent protein kinase. They also c ontained a normal level of VASP (vasodilator-stimulated phosphoprotein , a specific substrate of both cAMP- and cGMP-dependent protein kinase ), as well as a functionally intact prostaglandin E1-stimulated cAMP-m ediated VASP phosphorylation. In contrast, sodium nitroprusside-stimul ated VASP phosphorylation was severely impaired in these cGMP-dependen t protein kinase-deficient platelets, despite an exaggerated cGMP resp onse to sodium nitroprusside. Furthermore, whereas selective activatio n of the cGMP-dependent protein kinase by 8-(4-chlorophenylthio)-cGMP strongly inhibited the ADP- or thrombin-evoked calcium mobilization fr om intracellular stores in normal platelets, this agonist-evoked calci um response was not inhibited by the cGMP analog in cGMP-dependent pro tein kinase-deficient platelets. The results demonstrate a defect in t he nitrovasodilator-/cGMP-regulated signal transduction system in huma n platelets from some patients with myeloproliferative disorders, and underscore that a cGMP-dependent protein kinase regulatory system, dis tinct from that of cAMP-dependent protein kinase or other cGMP-depende nt effectors is operative in normal human platelets.