Molecular genetics of paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by the clonal expansion of glycosylphosphatidylinositol (GPI)-deficient cells that leads to complement-mediated hemolysis. A somatic mutation in the PIG-A gene involved in GPI biosynthesis causes a deficiency of GPI-anchored proteins. However, it is evident that the clonal expansion of GPI-deficient cells is not caused by only the PIG-A mutation and that other changes should be involved in the development of PNH. Some patients with aplastic anemia (AA) develop PNH. Furthermore, it has been reported that most patients with AA and refractory anemia (RA) who carry HLA-DRB1*15 and show a good response to immunosuppressive therapies have an expanded population of GPI-deficient clones. This finding, together with recent data showing resistance of GPI-deficient cells to cytotoxic cells, suggests that GPI-deficient cells escape immunologic attack and are positively selected in the autoimmune environment. However, GPI-deficient clones found in AA and RA are generally small and do not increase to near-complete dominance. Therefore, 1 or more additional genetic abnormalities that confer the growth phenotype on GPI-deficient cells are probably required for fully developed PNH or so-called florid PNH. The next 10 years should witness the discovery of the molecular mechanisms of immunologic selection and the identification of abnormalities involved in the further clonal expansion of PNH cells.