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STEM CELL GENETICS AND GENOMICS

On the Origin of Multiple Mutant Clones in Paroxysmal Nocturnal Hemoglobinuria

^aProgram for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, USA;
^bApplications of Theoretical Physics Group, Centro de Fisica Teorica e Computational & Departamento de Física da Faculdade de Ciências, Lisboa Codex, Portugal;
^cDivision of Hematology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

Correspondence: David Dingli, M.D., Ph.D., Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA. Telephone: 507 284 3417; Fax: 507 266 4972; e-mail: dingli.david{at}mayo.edu

Received June 1, 2007; accepted for publication August 14, 2007.
First published online in STEM CELLS EXPRESS   September 6, 2007.



The pool of hematopoietic stem cells that actively contributes to hematopoiesis is small, and the cells replicate slowly. Patients with paroxysmal nocturnal hemoglobinuria invariably have a mutation in the PIG-A gene, and many have more than one clone of PIG-A mutated cells. Typically there is a dominant clone and a smaller second clone. By using 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.

Disclosure of potential conflicts of interest is found at the end of this article.

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]

				R. A. Brodsky Paroxysmal Nocturnal Hemoglobinuria: Stem Cells and Clonality Hematology, January 1, 2008; 2008(1): 111 - 115. [Abstract] [Full Text] [PDF]