Paroxysmal nocturnal hemoglobinuria: new insights from murine Pig-a-deficient hematopoiesis

A large fraction of the hematopoietic cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are deficient in membrane expression of glycosylphosphatidylinositol-anchored proteins (GPI-APs). Current evidence suggests that this deficiency is sufficient to account for the hemolytic and thrombotic manifestations of this disease but not for its frequent association with aplastic anemia, an autoimmune disorder in which the patients' own hematopoietic progenitor cells are the target. Mutations in X-linked gene PIG-A, encoding one of several enzymes required for the biosynthesis of the glycophosphatidylinositol anchor, have been found in all PNH patients studied to date. Recent experiments with murine Pig-a knock-out embryonic stem cells show that although embryogenesis is critically dependent on normal GPI-AP expression, Pig-a-deficient cells can undergo apparently normal hematopoietic differentiation if they develop in a GPI-AP-replete environment. Thus, in an in vitro mouse model of PNH, Pig-a mutations confer no gross proliferative or differentiative advantage or disadvantage, suggesting an unidentified process selecting for these mutations in the bone marrow of patients with the PNH-aplastic anemia syndrome. The rescue of hematopoiesis observed in chimeric cultures of knock-out and normal cells was accompanied by intercellular transfer of GPI-AP, suggesting exciting new possibilities for future therapeutic manipulations in PNH patients.