Paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) are closely related, life-threatening bone marrow stem cell disorders. AA results from an immune-mediated attack against hematopoietic stem cells. PNH is a clonal hematopoietic stem cell disorder caused by a somatic mutation of the PIGA gone and may arise de novo or evolve from AA. The biochemical consequence of PIGA mutations is a global loss of glycosylphosphatidyl-inositol (GPI) anchors. We have shown that the GPI-anchor is the receptor for the channel forming toxin aerolysin and that PNH cells are uniquely resistant to aerolysin. A novel diagnostic assay using aerolysin to detect PNH cells has demonstrated that the majority of AA patients harbor small populations of PNH cells. We have also shown that high-dose cyclophosphamide (CY) can lead to durable treatment-free remissions in the majority of patients with AA. The objective of these studies is to explore the relationship between AA and PNH and to elucidate the mechanism of clonal dominance in PNH. We will directly test whether PNH gains clonal dominance through immunologic escape or whether PIGA mutations themselves give HSCs an intrinsic survival advantage. The use of PNH as a model to study clonal expansion and clonal progression should give insight into other clonal hematopoietic diseases such as myelodysplastic syndromes and leukemogenesis. Specfici Aim 1: Detect PIGA mutations in normal human HSC.
Specific Aim 2 : Study the relationship between AA and PNH.

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National Cancer Institute (NCI)
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