GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHOR-DEFICIENT MICE - IMPLICATIONS FORCLONAL DOMINANCE OF MUTANT-CELLS IN PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by complement-mediated hemolysis. Ab normal hematopoietic cells from patients with PNH are deficient in gly cosylphosphatidylinositol (GPI)-anchored proteins and clonally dominat e various hematopoietic lineages in the bone marrow and the peripheral blood, Analysis of many patients with PNH has showed that somatic mut ation in the X-linked gene PIG-A is responsible for the GPI-anchor def iciency in PNH, The PIG-A mutation must also be relevant to the clonal dominance of GPI-anchor deficient (GPI(-)) blood cells because two or more PIG-A mutant clones become dominant in many patients. However, w hether the PIG-A mutation alone is sufficient for clonal dominance is not known. To address this question, we generated chimeric mice using Pig-a (the murine homologue of PIG-A) disrupted embryonic stem (ES)cel ls, in which the animals are chimeric with respect to the surface expr ession of GPI-anchored proteins. The chimerism of hematopoietic and no nhematopoietic tissues in such mice was always low, suggesting that th e higher contribution of Pig-a disrupted GPI(-) cells had a lethal eff ect on the chimera. GPI(-) cells appeared in the peripheral blood of s ome of the chimeric mice. However, the percentage of GPI(-) erythrocyt es did not increase for 10 months after birth, implying that the Pig-a mutation alone does not immediately cause the clonal dominance of GPI (-) blood cells; another pathologic or physiologic change(s) in the he matopoietic environments or in the clone itself may be necessary. (C) 1996 by The American Society of Hematology.