TY - JOUR
T1 - Neutral evolution in paroxysmal nocturnal hemoglobinuria
AU - Dingli, David
AU - Luzzatto, Lucio
AU - Pacheco, Jorge M.
PY - 2008/11/25
Y1 - 2008/11/25
N2 - 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.
AB - 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.
KW - Hematopoiesis
KW - Mathematical modeling
KW - Mutation
KW - Stem cells
KW - Stochastic dynamics
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U2 - 10.1073/pnas.0802749105
DO - 10.1073/pnas.0802749105
M3 - Article
C2 - 19011109
AN - SCOPUS:57449083619
SN - 0027-8424
VL - 105
SP - 18496
EP - 18500
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 47
ER -