PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA - NEW INSIGHTS FROM MURINE PIG-A-DEFICIENT HEMATOPOIESIS

A large fraction of the hematopoietic cells of patients with paroxysma l nocturnal hemoglobinuria (PNH) are deficient in membrane expression of glycosylphosphatidylinositol-anchored proteins (GPI-APs). Current e vidence suggests that this deficiency is sufficient to account for the hemolytic and thrombotic manifestations of this disease but not for i ts frequent association with aplastic anemia, an autoimmune disorder i n which the patient's own hematopoietic progenitor cells are the targe t. Mutations in the X-linked gene PIG-A, encoding one of several enzym es required for the biosynthesis of the glycophosphatidylinositol anch or, have been found in all PNH patients studied to date. Recent experi ments with murine Pig-a knock-out embryonic stem cells show that altho ugh embryogenesis is critically dependent on normal GPI-AP expression, Pig-a-deficient cells can undergo apparently normal hematopoietic dif ferentiation if they develop in a GPI-AP-replete environment. Thus, in an in vitro mouse model of PNH, Pig-a mutations confer no gross proli ferative or differentiative advantage or disadvantage, suggesting an u nidentified process selecting for these mutations in the bone marrow o f patients with the PNH-aplastic anemia syndrome. The rescue of hemato poiesis observed in chimeric cultures of knock-out and normal cells wa s accompanied by intercellular transfer of GPI AP, suggesting exciting new possibilities for future therapeutic manipulations in PNH patient s.