Neutral evolution in paroxysmal nocturnal hemoglobinuria

David Dingli, Lucio Luzzatto, Jorge M. Pacheco

Research output: Contribution to journalArticle

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)18496-18500
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number47
DOIs
StatePublished - Nov 25 2008

Keywords

  • Hematopoiesis
  • Mathematical modeling
  • Mutation
  • Stem cells
  • Stochastic dynamics

ASJC Scopus subject areas

  • General

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