Abstract |
Paroxysmal nocturnal hemoglobinuria is an acquired hematopoietic stem cell (HSC) disorder characterized by the partial or complete deficiency of glycosyl-phosphatidylinositol ( GPI)-linked membrane proteins, which leads to intravascular hemolysis. A loss of function mutation in the PIG-A gene, required for GPI biosynthesis, explains how the deficiency of many membrane proteins can result from a single genetic event. However, to date the mechanism of expansion of the GPI(-) clone has not been fully understood. Two hypotheses have been proposed: A selective advantage of GPI(-) cells because of a second mutation or a conditional growth advantage of GPI(-) cells in the presence of an immune attack on normal (GPI(+)) HSCs. Here, we explore a third possibility, whereby the PNH clone does not have a selective advantage. Simulations in a large virtual population accurately reproduce the known incidence of the disease; and the fit is optimized when the number of stem cells is decreased, reflecting a component of bone marrow failure in PNH. The model also accounts for the occurrence of spontaneous cure in PNH, consequent on clonal extinction. Thus, a clonal advantage may not be always necessary to explain clonal expansion in PNH.
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Authors | David Dingli, Lucio Luzzatto, Jorge M Pacheco |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 105
Issue 47
Pg. 18496-500
(Nov 25 2008)
ISSN: 1091-6490 [Electronic] United States |
PMID | 19011109
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Membrane Proteins
- phosphatidylinositol glycan-class A protein
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Topics |
- Adult
- Hematopoiesis
- Hematopoietic Stem Cells
(physiology)
- Hemoglobinuria, Paroxysmal
(genetics, physiopathology)
- Humans
- Membrane Proteins
(genetics)
- Models, Theoretical
- Mutation
- Stochastic Processes
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