On the Origin of Multiple Mutant Clones in Paroxysmal Nocturnal Hemoglobinuria

¹ Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138, USA
² Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138, USA; ATP-Group, CFTC Departamento de Física da Faculdade de Ciências, P-1649-003 Lisboa Codex, Portugal
³ Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138, USA; Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

^* To whom correspondence should be addressed. E-mail: dingli.david{at}mayo.edu.

	Abstract

The pool of hematopoietic stem cells that actively contributes to hematopoiesis is small and the cells replicate slowly. Patients with paroxysmal nocturnal hemoglobinuria (PNH) invariably have a mutation in the PIG-A gene and many have more than 1 clone of PIG-A mutated cells. Typically there is a dominant clone and a smaller, second clone. By utilizing a combination of stochastic dynamics and models of hematopoiesis, we show that it is very unlikely that more than one PIG-A mutated clone arises at the level of the hematopoietic stem cells. More likely the smaller clone develops in the progenitor cell pool that would be expected to contribute to hematopoiesis for a shorter period of time. We provide estimates for the duration of these contributions and testable hypotheses that can shed important insights on this acquired hematopoietic stem cell disorder.

This article has been cited by other articles:

				D. Dingli, L. Luzzatto, and J. M. Pacheco Neutral evolution in paroxysmal nocturnal hemoglobinuria PNAS, November 25, 2008; 105(47): 18496 - 18500. [Abstract] [Full Text] [PDF]