Neutral evolution in paroxysmal nocturnal hemoglobinuria.
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.
Dingli
David
D
Division of Hematology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA. dingli.david@mayo.edu
Luzzatto
Lucio
L
Pacheco
Jorge M
JM
D000328:Adult; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008962:Models, Theoretical; D009154:Mutation; D013269:Stochastic Processes
D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein