Abstract
BackgroundLarge clonal populations of cells bearing PIG-A mutations are the sine qua non of PNH, but the PIG-A mutation itself is insufficient for clonal expansion. The association between PNH and aplastic anemia supports the immune escape model, but not all PNH patients demonstrate a history of aplasia; therefore, second genetic hits driving clonal expansion have been postulated. Based on the previous identification of JAK2 mutations in patients with a myeloproliferative/PNH overlap syndrome, we considered TET2 as a candidate gene in which mutations might be contributing to clonal expansion.MethodsHere we sequenced the TET2 and JAK2 genes in 19 patients with large PNH clones.ResultsWe found one patient with a novel somatic nonsense mutation in TET2 in multiple hematopoietic lineages, which was detectable upon repeat testing. This patient has had severe thromboses and has relatively higher peripheral blood counts compared with the other patients—but does not have other features of a myeloproliferative neoplasm.ConclusionsWe conclude that mutations in TET2 may contribute to clonal expansion in exceptional cases of PNH.
Highlights
Large clonal populations of cells bearing PIG-A mutations are the sine qua non of Paroxysmal nocturnal hemoglobinuria (PNH), but the PIG-A mutation itself is insufficient for clonal expansion
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement mediated hemolysis, immune mediated marrow failure, and an expansion in the marrow of a stem cell with an acquired somatic mutation in PIG-A [1]. This gene is essential for the biosynthesis of glycosylphosphatidylinositol (GPI), and circulating cells derived from the PNH clone are missing all GPI-linked proteins, including the complement inhibitors CD55 and CD59 [2]
Platelets derived from the mutant stem cell clone have the same surface defect as red cells, but here the effect of uninhibited complement may primarily lead to a state of activation, explaining the marked hypercoagulable state seen in this disorder
Summary
Large clonal populations of cells bearing PIG-A mutations are the sine qua non of PNH, but the PIG-A mutation itself is insufficient for clonal expansion. Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement mediated hemolysis, immune mediated marrow failure, and an expansion in the marrow of a stem cell with an acquired somatic mutation in PIG-A [1] This gene is essential for the biosynthesis of glycosylphosphatidylinositol (GPI), and circulating cells derived from the PNH clone are missing all GPI-linked proteins, including the complement inhibitors CD55 and CD59 [2]. The immune escape model [14] posits that the PIG-A gene mutation represents the “first hit”, and aplastic anemia (AA)—which selects for GPI (−) stem cells—represents the necessary “second hit” In support of this model, the GPI-anchor can fit into the groove of the HLA-like molecule CD1d [15], there is recent evidence that GPI itself may be the auto-antigen [16], and lymphocyte cultures can be raised to selectively kill GPI (+) cells [17]. The immune escape model is supported by the demonstration of oligoclonal T cell
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