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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2541-2550
The PIG-A Mutation and Absence of Glycosylphosphatidylinositol-Linked
Proteins Do Not Confer Resistance to Apoptosis in Paroxysmal
Nocturnal Hemoglobinuria
Russell E. Ware,
Jun-ichi Nishimura,
M. Anthony Moody,
Clay Smith,
Wendell F. Rosse, and
Thad A. Howard
From the Division of Hematology/Oncology, Department of Pediatrics;
the Division of Hematology; and the Division of Medical Oncology and
Transplantation, Department of Medicine, Duke University Medical
Center, Durham, NC.
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal stem cell
disorder characterized by complement-mediated hemolysis and deficient
hematopoiesis. The development of PNH involves an acquired mutation in
the X-linked PIG-A gene, which leads to incomplete bioassembly of
glycosylphosphatidylinositol (GPI) anchors and absent or reduced
surface expression of GPI-linked proteins. The origin and mechanisms by
which the PNH clone becomes dominant are not well understood, but
recently resistance to apoptosis has been postulated. To test the
hypothesis that the PIG-A mutation and absence of GPI-linked surface
proteins directly confer resistance to apoptosis, we isolated
peripheral granulocytes from 26 patients with PNH and 20 normal
controls and measured apoptosis induced by serum starvation.
Granulocytes from patients with PNH were relatively resistant to
apoptosis (38.8% ± 14.1%) as compared with granulocytes from
controls (55.0% ± 12.0%, P < .001). However, this
resistance to apoptosis was not related to the dominance of the PNH
clone because patients with a low percentage of GPI-deficient granulocytes had a similar rate of apoptosis as those with a high percentage of GPI-deficient granulocytes. Similarly, the resistance to
granulocyte apoptosis was not influenced by the degree of neutropenia or a prior history of aplastic anemia. To investigate formally the
importance of GPI-linked surface proteins in apoptosis, we introduced
the PIG-A cDNA sequence into the JY5 GPI-negative B-lymphoblastoid cell
line using two different methods: (1) stable transfection of a plasmid
containing PIG-A, and (2) stable transduction of a retroviral vector
containing PIG-A. We then measured rates of apoptosis induced either by
Fas antibody, serum starvation, or  -irradiation. With each stimulus,
apoptosis of JY5 with stable surface expression of GPI-linked proteins
was not statistically different from the parent JY5 cell line or the
JY25 (GPI-positive) cell line. Our data confirm that granulocytes from
patients with PNH have a relative resistance to apoptosis as compared
with normal granulocytes. However, this resistance does not vary with
the level of expression of GPI-linked proteins, and stable introduction of PIG-A cDNA with correction of GPI-linked surface expression does not
change the rate of apoptosis. Taken together, our data do not support
the hypothesis that the PIG-A mutation and absence of GPI-linked
surface proteins directly confer resistance to apoptosis in PNH. We
conclude that the resistance to apoptosis in PNH is not related to the
PIG-A mutation, indicating that other factors must be important in the
origin of this phenomenon and the clonal dominance observed in PNH.
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