RESISTANCE TO APOPTOSIS CAUSED BY PIG-A GENE-MUTATIONS IN PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic st em cell disorder resulting from mutations in an X-linked gene, PIG-A, that encodes an enzyme required for the first step in the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, PIG-A mutations result in absent or decreased cell surface expression of ali GPI-anchored pr oteins. Although many of the clinical manifestations (e.g., hemolytic anemia) of the disease can be explained by a deficiency of GPI-anchore d complement regulatory proteins such as CD59 and CD55, it is unclear why the PNH clone dominates hematopoiesis and why it is prone to evolv e into acute leukemia, me found that PIG-A mutations confer a survival advantage by making cells relatively resistant to apoptotic death. Wh en placed in serum-free medium, granulocytes and affected CD34(+) (CD5 9(-)) cells from PNH patients survived longer than their normal counte rparts, PNH cells were also relatively resistant to apoptosis induced by ionizing irradiation, Replacement of the normal PIG-A gene in PNH c ell lines reversed the cellular resistance to apoptosis, Inhibited apo ptosis resulting from PIG-A mutations appears to be the principle mech anism by which PNH cells maintain a growth advantage over normal proge nitors and could play a role in the propensity of this disease to tran sform into more aggressive hematologic disorders. These data also sugg est that GPI anchors are important in regulating apoptosis.