PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA - MOLECULAR PATHOGENESIS AND MOLECULAR THERAPEUTIC APPROACHES

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hemato logic stem cell disorder classified as an intravascular hemolytic anem ia. Abnormal blood cells are deficient in glycosylphosphatidyl inosito l (GPI)-anchored proteins. Deficiencies of GPI-anchored complement reg ulatory proteins, such as decay accelerating factor (DAF) and CD59, re nder red cells very sensitive to complement and result in complement-m ediated hemolysis and hemoglobinuria. In the affected hematopoietic ce lls from patients with PNH, the first step in biosynthesis of the GPI anchor is defective. Three genes are involved in this reaction step an d one of them, an X-linked gene termed PIG-A, is mutated in affected c ells. Granulocytes and lymphocytes from the same patient have the same mutation, indicating that a somatic PIG-A mutation occurs in hematopo ietic stem cells. The PIG-A gene is mutated in all patients with PNH r eported to date.We review these recent advances in the understanding o f the molecular pathogenesis of PNH. Furthermore, we present an hypoth esis regarding the predominance of the PNH clone, caused by positive s election by hematopoietic suppressive cytokines, such as transforming growth factor (TGF)-beta. In addition, we discuss the possibility of c ure for PNH through molecular therapeutic strategy using gene transfer . techniques.