IDENTIFICATION OF A SUBGROUP OF MYELODYSPLASTIC PATIENTS WITH A NEUTROPHIL STIMULATION-SIGNALING DEFECT

f-Met-Leu-Phe-stimulated luminol-enhanced chemiluminescence was found to be repeatedly defective in some MDS patients. This defect was not a ttributed to myeloperoxidase deficiency, nor to a defect in NADPH oxid ase function, because PMA chemiluminescence was found to be normal in these individuals. An arbitrary value of 7 mV (half the mean control v alue) was chosen to subdivide the group: MDS patients with values <7 m V had a mean f-Met-Leu-Phe chemiluminescence response of 2.5 +/- 0.5 c ompared to MDS patients with Values >7 mV who had a mean response of 1 5.6 +/- 1.6 mV, P<0.01 (healthy controls 14 +/-2 mV). The characterist ics of the fMet-Leu-Phe receptor and initial calcium flux results sugg ested that the receptor itself was normal in number and function in lo w f-Met-Leu-Phe responders. The rate of superoxide generation, which i s calcium-dependent, was also found to be in the normal range in low f -Met-Leu-Phe responders, although total superoxide production was redu ced in some of these patients. When MDS neutrophils with a low f-Met-L eu-Phe response were stimulated with PMA, chemiluminescence was normal , suggesting normal activity of the NADPH-oxidase complex. Furthermore , myeloperoxidase activity was reduced in only three out of the 11 low f-Met-Leu-Phe responders. Following priming with GM-CSP, f-Met-Leu-Ph e chemiluminescence was 27 +/- 1.6 mV in low f-Met-Leu-Phe responders compared to controls (87.7 +/- 11 mV, P<0.005). Thus, although respons es were improved, they were not as marked as in control neutrophils. T hese data suggest that a subgroup of MDS patients have a low f-Met-Leu -Phe chemiluminescence response which is not due to a defect in the f- Met-Leu-Phe receptor or oxidase activity, and in the majority of cases MPO activity is normal. initial patient survival data suggest that th ese patients may have an increased risk of infective mortality. It is proposed that defective f-Met-Leu-Phe chemiluminescence results from a putative defect in cell-signalling mechanism upstream of PKC, and GM- CSF priming only partially improves responsiveness.