Abstract
Patients with paroxysmal nocturnal hemoglobinuria (PNH) have one or a few clones of mutant hematopoietic stem cells defective in glycosylphosphatidylinositol (GPI) synthesis due to somatic mutation in the X-linked gene PIG-A. The mutant stem cell clone dominates hematopoiesis, the mechanism of which is unclear. To test whether lacks of multiple GPI-anchored proteins result in dysregulation and expansion of stem cells, we generated mice in which GPI-anchor negative cells are present only in hematopoietic system. We transplanted lethally irradiated mice with female fetal liver cells bearing one allele of Piga gene disrupted by conditional gene targeting. Due to the X-chromosome inactivation, a significant fraction of the hematopoietic stem cells in fetal livers were GPI-anchor negative. In the transplanted mice, cells of all hematopoietic lineages contained GPI-anchor negative cells. The proportions of GPI-anchor negative cells in various blood cell lineages were stable for 42 weeks, indicating that Piga mutation alone does not cause dominance of the mutant stem cells and that other changes are involved in pathogenesis of PNH.
Published Version
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