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Paroxysmal Nocturnal Hemoglobinuria: Stem Cells and Clonality

Correspondence: Robert A. Brodsky, MD, Ross Research Building, Room 1025, 720 Rutland Avenue, Baltimore, MD 21205-2196; Phone: 410 502-2546; Fax: 410 955-0185; e-mail: brodsro{at}jhmi.edu.

Abstract

Paroxysmal nocturnal hemoglobinuria is a clonal hematopoietic stem cell disease that manifests with intravascular hemolysis, bone marrow failure, thrombosis, and smooth muscle dystonias. The disease can arise de novo or in the setting of acquired aplastic anemia. All PNH patients to date have been shown to harbor PIG-A mutations; the product of this gene is required for the synthesis of glycosylphosphatidylinositol (GPI) anchored proteins. In PNH patients, PIG-A mutations arise from a multipotent hematopoietic stem cell. Interestingly, PIG-A mutations can also be found in the peripheral blood of most healthy controls; however, these mutations arise from progenitor cells rather than multipotent hematopoietic stem cells and do not propagate the disease. The mechanism of whereby PNH stem cells achieve clonal dominance remains unclear. The leading hypotheses to explain clonal outgrowth in PNH are: 1) PNH cells evade immune attack possibly, because of an absent cell surface GPI-AP that is the target of the immune attack; 2) The PIG-A mutation confers an intrinsic resistance to apoptosis that becomes more conspicuous when the marrow is under immune attack; and 3) A second mutation occurs in the PNH clone to give it an intrinsic survival advantage. These hypotheses may not be mutually exclusive, since data in support of all three models have been generated.

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