![]() In most PNH patients, GPI-anchor deficiency is caused by somatic mutations in phosphatidylinositol glycan anchor biosynthesis class A ( PIGA), an X-linked gene required for GPI anchor biosynthesis ( 4– 6) ( Figure 1). Paul Strübing, it was over a century later when the cause of PNH was identified as an absence of a group of membrane proteins attached to the cell surface by glycosylphosphatidylinositol (GPI) anchors ( 1– 3). Although PNH was recognized in the clinic as early as 1882 by Dr. Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, life-threatening blood disease characterized by hemolysis, propensity for blood clotting, and bone marrow failure ( 1). Here, we critically review published data on PNH cell biology and clonal expansion and highlight limitations and opportunities to further our understanding of the emergence of PNH clones. Recent advancements in disease models and immunologic technologies, together with the growing understanding of autoimmune marrow failure, offer new opportunities to evaluate the mechanisms of clonal expansion in PNH. However, to what extent these contribute to PNH cell selection in patients continues to be a matter of active debate. Landmark studies identified several potential mechanisms which can promote PNH clonal expansion. Historical models of PNH in mice and the more recent PNH model in rhesus macaques showed that GPI (-) cells reconstitute near-normal hematopoiesis but have no intrinsic growth advantage and do not clonally expand over time. In PNH patients, PIGA-mutant, GPI (-) hematopoietic cells clonally expand to make up a large portion of patients’ blood production, yet mechanisms leading to clonal expansion of GPI (-) cells remain enigmatic. The loss of two GPI-anchored surface proteins, CD55 and CD59, from red blood cells causes unregulated complement activation and hemolysis in classical PNH disease. Ubiquitous in eukaryotes, GPI anchors are a group of conserved glycolipid molecules responsible for attaching nearly 150 distinct proteins to the surface of cell membranes. PNH patients develop somatic loss-of-function mutations in phosphatidylinositol N-acetylglucosaminyltransferase subunit A gene ( PIGA), required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors. Paroxysmal Nocturnal Hemoglobinuria (PNH) is a disease as simple as it is complex. 2Comprehensive Bone Marrow Failure Center, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States. ![]() 1Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States.Colden 1,2, Sushant Kumar 1,2, Bolormaa Munkhbileg 1,2 and Daria V.
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