Different roles of glycosylphosphatidylinositol in various hematopoietic cells as revealed by a mouse model of paroxysmal nocturnal hemoglobinuria

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have one or a few c lones of mutant hematopoietic stem cells defective in glycosylphosphatidyli nositol (GPI) synthesis as a result of somatic mutation in the X-linked gen e 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 r esults in dysregulation and expansion of stem cells, we generated mice in w hich GPI-anchor negative cells are present only in the hematopoietic system . We transplanted lethally irradiated mice with female fetal liver cells be aring one allele of the Piga gene disrupted by conditional gene targeting. Because of the X-chromosome inactivation, a significant fraction of the hem atopoietic stem cells in fetal livers was GPI-anchor negative. In the trans planted mice, cells of all hematopoietic lineages contained GPI-anchor nega tive cells, The percentage of GPI-anchor negative cells was much higher in T lymphocytes including immature thymocytes than in other cell types, sugge sting a regulatory role for GPI-anchored proteins at an early stage of T-ly mphocyte development. However, the proportions of GPI-anchor negative cells in various blood cell lineages were stable over a period of 42 weeks, indi cating that Piga mutation alone does not account for the dominance of the m utant stem cells and that other phenotypic changes are involved in pathogen esis of PNH, (C) 1999 by The American Society of Hematology.