Impaired activation of phospholipase D in polycythaemia vera-implications for the pathogenesis of the disease?

A series of studies have demonstrated a stimulus-specific defect in PMN oxidative metabolism after stimulation with surface receptor dependent stimuli such as fMLP, leukotriene B4 and platelet activating factor (PAF), whereas the response to phorbol myristate acetate was normal. Having discovered this defect, studies of the stimulus response coupling for oxidative responses were performed showing a normal interaction of fMLP with it's receptor, as well as an intact activation of phospholipase C, as measured by the generation of 1,4,5-inositoltrisphosphate, and the subsequent rise of intracellular calcium. In contrast, the formation of diacylglycerol and phosphatidylethanol was decreased in PV PMN, denoting an impaired activation of phospholipase D (PLD). It was shown by flow cytometry analyses that the hampered oxidative response was present both in single PMN and monocytes. Moreover, platelets from PV patients, whose PMN exhibit a lower oxidative response to PAF, also have a diminished aggregatory response to PAF. Thus three different cell lineages in PV have been revealed to respond abnormally to surface receptor dependent stimuli, indicating that the proposed impairment of PLD might be relevant for changes in the malignant stem cell clone. Since phosphatidic acid, produced as a result of PLD activation, may be implicated in the regulation of several oncogenes, perturbations of the PLD system could theoretically be important for the development of PV.