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Blood, 15 May 2005, Vol. 105, No. 10, pp. 3848-3854.
Prepublished online as a Blood First Edition Paper on February 1, 2005; DOI 10.1182/blood-2004-04-1472.
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Submitted April 19, 2004
Accepted January 25, 2005
PIG-A mutations in normal hematopoiesis
Rong Hu, Galina L Mukhina, Steven Piantadosi, Jamie P Barber, Richard J Jones, and Robert A Brodsky*
School of Medicine, Division of Hematology, Johns Hopkins University, Baltimore, MD, USA
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
* Corresponding author; email: brodsro{at}jhmi.edu.
Paroxysmal nocturnal hemoglobinuria (PNH) is caused by PIG-A mutations in hematopoietic stem cells (HSCs). PIG-A mutations have been found in granulocytes from most normal individuals, suggesting that these spontaneous PIG-A mutations are important in the pathogenesis of PNH. It remains unclear if these PIG-A mutations have relevance to those found in PNH. We isolated CD34+ progenitors from 4 PNH patients and 27 controls. The frequency of PIG-A mutant progenitors was determined by assaying for colony forming cells (CFC) in methylcellulose containing toxic doses of aerolysin (1 x 10-9 M). GPI-anchored proteins serve as receptors for aerolysin; thus, PNH cells are resistant to aerolysin. The frequency of aerolysin resistant CFC was 14.7±4.0 x 10-6 in the bone marrow of healthy donors and was 57.0±6.7 x 10-6 from mobilized peripheral blood. DNA was extracted from individual day 14 aerolysin resistant CFC and the PIG-A gene was sequenced to determine clonality. Aerolysin resistant CFC from PNH patients exhibited clonal PIG-A mutations. In contrast, PIG-A mutations in the CFC from controls were polyclonal, and did not involve T cells. Our data confirm the findings that PIG-A mutations are relatively common in normal hematopoiesis; however, the findings suggest that these mutations occur in differentiated progenitors rather than HSC.
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