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A new hint to clonal dominance in PNH.

Hematol Oncol Stem Cell Ther 5(3) Third Quarter 2012 hemoncstem.edmgr.com 162 Paroxysmal nocturnal hemoglobinuria (PNH) arises in a hematopoietic stem cell due to an acquired somatic mutation in the phosphatidylinositol glycan class A (PIGA) gene that resides in the short arm of the X chromosome. Affected progeny cells are incapable of biosynthesis of the glycosylphosphatidylinositol (GPI)-anchor and lack from their surface all GPIanchored proteins (GPI-AP). However, expansion of a PNH clone is not the simple result of the mutational event, as PIGA-mutant cells exist in small numbers in normal individuals. In PNH, clonal expansion of GPIAP-deficient cells leads to a syndrome characterized by hemolytic anemia, marrow failure, and venous thrombosis. Intravascular hemolysis results from failure of complement inactivation by CD59 (MIRL) and CD55 (DAF), missing from the surface of GPI-AP-deficient erythrocytes. In vivo expansion of dominant T-cell clones can reflect an antigen-driven immune response.1 Clinical overlap with immune-mediated aplastic anemia (AA), association with particular HLA-DR1501 and abnormalities of the immune system such as oligoclonality of the TCR repertoire support the hypothesis of an autoimmune pathophysiology of PNH. Recently, increased susceptibility to apoptosis of normal GPI+ cells has been shown to be responsible for preferential growth of GPIcells in PNH patients.2 Apoptosis of targets may be a consequence of T-cell mediated cytotoxicity.3 In this issue of Hematology/Oncology and Stem Cell Therapy, Kunyaboon et al report results of a study designed to explore the roles of differential apoptosis and CD8+ lymphocytes in the selection of PNH clones in patients with PNH to demystify the mechanisms of PNH clonal dominance.4 They have elegantly demonstrated that increased apoptosis of GPI+ blood cells is probably an important factor in selection and expansion of PNH clones. In addition, they concluded that mononuclear cells and possibly CD8+ lymphocytes may play a role in this phenomenon.4 Using an annexin-V based apoptosis assay, they demonstrated that in PNH, CD59+ granulocytes exhibited significantly A New Hint to Clonal Dominance in PNH