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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 2963-2970
Different Roles of Glycosylphosphatidylinositol in Various
Hematopoietic Cells as Revealed by a Mouse Model of Paroxysmal
Nocturnal Hemoglobinuria
Y. Murakami,
T. Kinoshita,
Y. Maeda,
T. Nakano,
H. Kosaka, and
J. Takeda
From Departments of Immunoregulation and Molecular Cell Biology,
Research Institute for Microbial Diseases, Osaka University, and
Departments of Dermatology and Environmental Medicine, Osaka University
Medical School, Suita, Osaka, Japan.
Patients with paroxysmal nocturnal hemoglobinuria (PNH) have one or
a few clones of mutant hematopoietic stem cells defective in
glycosylphosphatidylinositol (GPI) synthesis as a result of somatic
mutation in the X-linked gene PIG-A. The mutant stem cell clone
dominates hematopoiesis by a mechanism that is unclear. To
test whether a lack of multiple GPI-anchored proteins results in
dysregulation and expansion of stem cells, we generated mice in which
GPI-anchor negative cells are present only in the hematopoietic system.
We transplanted lethally irradiated mice with female fetal liver cells
bearing one allele of the Piga gene disrupted by conditional gene targeting. Because of the X-chromosome inactivation, a significant fraction of the hematopoietic stem cells in fetal livers was GPI-anchor negative. In the transplanted mice, cells of all hematopoietic lineages
contained GPI-anchor negative cells. The percentage of GPI-anchor
negative cells was much higher in T lymphocytes including immature
thymocytes than in other cell types, suggesting a regulatory role for
GPI-anchored proteins at an early stage of T-lymphocyte development.
However, the proportions of GPI-anchor negative cells in various blood
cell lineages were stable over a period of 42 weeks, indicating that
Piga mutation alone does not account for the dominance of the
mutant stem cells and that other phenotypic changes are involved in
pathogenesis of PNH.
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