title: Differential apoptosis and Fas expression on GPI-negative and GPI-positive stem cells: a mechanism for the evolution of paroxysmal nocturnal haemoglobinuria.
abstract: Paroxysmal nocturnal haemoglobinuria (PNH) has a dual pathogenesis. PIG-A mutations generate clones of haemopoietic stem cells (HSC) lacking glycosylphosphatidylinositol (GPI)-anchored proteins and, secondly, these clones expand because of a selective advantage related to bone marrow failure. The first aspect has been elucidated in detail, but the mechanisms leading to clonal expansion are not well understood. We have previously shown that apoptosis and Fas expression in HSC play a role in bone marrow failure during aplastic anaemia. We have now investigated apoptosis in PNH. Ten patients were studied. Apoptosis, measured by flow cytometry, was significantly higher among CD34+ cells from patients compared with healthy controls. Fas expression was also increased. Cells that were stained for CD34, CD59 and apoptosis showed a significantly lower apoptosis in CD34+/CD59- compared with CD34+/CD59+ cells from the same patient. In three patients, staining for CD34, CD59 and Fas revealed lower Fas expression on CD34+/CD59- cells. Differential apoptosis of CD34+/CD59- HSC may be sufficient in itself to explain the expansion of PNH clones in the context of aplastic anaemia. In addition to demonstrating a basic mechanism underlying PNH clonal expansion, these results suggest further hypotheses for the evolution of PNH, based on the direct or indirect resistance of GPI-negative HSC to pro-inflammatory cytokines.
authors: Department of Cellular and Molecular Medicine, St George's Hospital Medical School, London, UK.
authors: Medhat M
authors: MM
authors: Ismail
authors: Jennifer A
authors: JA
authors: Tooze
authors: Julie A
authors: JA
authors: Flynn
authors: Edward C
authors: EC
authors: Gordon-Smith
authors: Frances M
authors: FM
authors: Gibson
authors: Tim R
authors: TR
authors: Rutherford
authors: Modupe O
authors: MO
authors: Elebute
mesh_terms: D000293:Adolescent; D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D018957:CD59 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006457:Hemoglobinuria, Paroxysmal / Q000276:immunology / Q000473:pathology*; D006801:Humans; D008297:Male; D013234:Stem Cells / Q000276:immunology / Q000473:pathology*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; D018957:CD59 Antigens; D017261:Glycosylphosphatidylinositols; D019014:fas Receptor