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

Area of Science:

• Hematology
• Cellular Biology
• Biochemistry

Background:

• Neutrophil (PMN) oxidative metabolism is crucial for immune response.
• Stimulus-specific defects in PMN metabolism have been observed in polycythemia vera (PV).

Purpose of the Study:

• To investigate the underlying molecular defect in PMN oxidative metabolism in PV.
• To explore the role of phospholipase D (PLD) in PV pathogenesis.

Main Methods:

• Stimulation of PMN with various agents (fMLP, LTB4, PAF, PMA).
• Measurement of oxidative metabolites, intracellular calcium, inositoltrisphosphate, diacylglycerol, and phosphatidylethanol.
• Flow cytometry analysis of PMN and monocytes.
• Platelet aggregation studies.

Main Results:

• PV PMN exhibited a stimulus-specific defect in oxidative metabolism, normal in response to PMA but impaired with receptor-dependent stimuli.
• Normal fMLP receptor interaction, phospholipase C activation, and intracellular calcium rise were observed.
• Decreased diacylglycerol and phosphatidylethanol formation indicated impaired phospholipase D (PLD) activation in PV PMN.
• Impaired oxidative response and diminished platelet aggregation to PAF were noted in PV patients.
• Defective response to surface receptor-dependent stimuli was observed in PMN, monocytes, and platelets.

Conclusions:

• An impaired phospholipase D (PLD) activation is identified as the stimulus-specific defect in PV PMN oxidative metabolism.
• The findings suggest PLD impairment may be relevant to malignant stem cell clone changes in PV.
• Perturbations in the PLD system could theoretically contribute to the development of PV, potentially through oncogene regulation.