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Impaired hematopoiesis in paroxysmal nocturnal hemoglobinuria/aplastic
anemia is not associated with a selective proliferative defect in the
glycosylphosphatidylinositol-anchored protein-deficient clone
JP Maciejewski, EM Sloand, T Sato, S Anderson and NS Young
Hematology Branch, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, MD, USA.
Paroxysmal nocturnal hemoglobinuria (PNH) results from somatic mutations in
the PIG-A gene, leading to poor presentation of
glycosylphosphatidylinositol (GPI)-anchored surface proteins. PNH
frequently occurs in association with suppressed hematopoiesis, including
frank aplastic anemia (AA). The relationship between GPI- anchored protein
expression and bone marrow (BM) failure is unknown. To assess the
hematopoietic defect in PNH, the numbers of CD34+ cells, committed
progenitors (primary colony-forming cells [CFCs]), and long- term
culture-initiating cells (LTC-ICs; a stem cell surrogate) were measured in
BM and peripheral blood (PB) of patients with PNH/AA syndrome or patients
with predominantly hemolytic PNH. LTC-IC numbers were extrapolated from
secondary CFC numbers after 5 weeks of culture, and clonogenicity of
LTC-ICs was determined by limiting dilution assays. When compared with
normal volunteers (n = 13), PNH patients (n = 14) showed a 4.7-fold
decrease in CD34+ cells and an 8.2-fold decrease in CFCs. LTC-ICs in BM and
in PB were decreased 7.3-fold and 50-fold, respectively. Purified CD34+
cells from PNH patients had markedly lower clonogenicity in both primary
colony cultures and in the LTC-IC assays. As expected, GPI-anchored
proteins were decreased on PB cells of PNH patients. On average, 23% of
monocytes were deficient in CD14, and 47% of granulocytes and 58% of
platelets lacked CD16 and CD55, respectively. In PNH BM, 27% of CD34+ cells
showed abnormal GPI- anchored protein expression when assessed by CD59
expression. To directly measure the colony-forming ability of GPI-anchored
protein- deficient CD34+ cells, we separated CD34+ cells from PNH patients
for the GPI+ and GPI-phenotype; CD59 expression was chosen as a marker of
the PNH phenotype based on high and homogeneous expression on fluorescent
staining. CD34+ CD59+ and CD34+ CD59-cells from PNH/AA patients showed
similarly impaired primary and secondary clonogeneic efficiency. The
progeny derived from CD34+ CD59- cells were both CD59- and CD55-. A very
small population of CD34+ CD59- cells was also detected in some normal
volunteers; after sorting, these CD34+ CD59- cells formed normal numbers of
colonies, but their progeny showed lower CD59 levels. Our results are
consistent with the existence of PIG-A- deficient clones in some normal
individuals. In PNH/AA, progenitor and stem cells are decreased in number
and function, but the proliferation in vitro is affected similarly in
GPI-protein-deficient clones and in phenotypically normal cells. As
measured in the in vitro assays, expansion of PIG-A- clones appears not be
caused by an intrinsic growth advantage of cells with the PNH phenotype.
Volume 89,
Issue 4,
pp. 1173-1181,
02/15/1997
Copyright © 1997 by The American Society of Hematology
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