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Blood, 1 August 2002, Vol. 100, No. 3, pp. 1031-1037
RED CELLS
Decreased susceptibility of leukemic cells with PIG-A
mutation to natural killer cells in vitro
Shoichi Nagakura,
Sonoko Ishihara,
Daniel E. Dunn,
Jun-ichi Nishimura,
Tatsuya Kawaguchi,
Kentaro Horikawa,
Michihiro Hidaka,
Tadashi Kagimoto,
Nozomu Eto,
Hiroaki Mitsuya,
Taroh Kinoshita,
Neal S. Young, and
Hideki Nakakuma
From the Second Department of Internal Medicine,
Kumamoto University School of Medicine, Japan; Hematology Branch,
National Heart, Lung, and Blood Institute, National Institutes of
Health, Bethesda, MD; Department of Immunoregulation, Research
Institute for Microbial Diseases, Osaka University, Japan; Department
of Biochemistry and Applied Biosciences, Miyazaki University, Japan.
The cloning of the PIG-A gene has facilitated the
unraveling of the complex pathophysiology of paroxysmal nocturnal
hemoglobinuria (PNH). Of current major concern is the mechanism by
which a PNH clone expands. Many reports have suggested that an immune
mechanism operates to cause bone marrow failure in some patients with
PNH, aplastic anemia, and myelodysplastic syndromes. Because blood cells of PNH phenotype are often found in patients with these marrow
diseases, one hypothesis is that the PNH clone escapes immune attack,
producing a survival advantage by immunoselection. To test this
hypothesis, we examined the sensitivity of blood cells, with or without
PIG-A mutations, to killing by natural killer (NK) cells,
using 51Cr-release assay in vitro. To both peripheral blood
and cultured NK cells, PIG-A mutant cells prepared from
myeloid and lymphoid leukemic cell lines were less susceptible than
their control counterparts (reverted from the mutant cells by
transfection with a PIG-A cDNA). NK activity was completely
abolished with concanamycin A and by calcium chelation, indicating that
killing was perforin-dependent. There were no differences in major
histocompatibility (MHC) class I expression or sensitivity to either
purified perforin or to interleukin-2-activated NK cells between
PIG-A mutant and control cells. From these results, we
infer that PIG-A mutant cells lack molecules needed for NK
activation or to trigger perforin-mediated killing. Our experiments
suggest that PIG-A mutations confer a relative survival
advantage to a PNH clone, contributing to selective expansion of these
cells in the setting of marrow injury by cytotoxic lymphocytes.
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