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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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HEMATOPOIESIS
PIG-A mutations in normal hematopoiesis
Rong Hu,
Galina L. Mukhina,
Steven Piantadosi,
Jamie P. Barber,
Richard J. Jones, and
Robert A. Brodsky
From the Johns Hopkins University, School of Medicine, Division of Hematology, Baltimore, MD, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.
Paroxysmal nocturnal hemoglobinuria (PNH) is caused by phosphatidylinositol glycan–class A (PIG-A) mutations in hematopoietic stem cells (HSCs). PIG-A mutations have been found in granulocytes from most healthy 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 patients with PNH and 27 controls. The frequency of PIG-A mutant progenitors was determined by assaying for colony-forming cells (CFCs) in methylcellulose containing toxic doses of aerolysin (1 x 10-9 M). Glycosylphosphatidylinositol (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 CFCs and the PIG-A gene was sequenced to determine clonality. Aerolysin-resistant CFCs from patients with PNH exhibited clonal PIG-A mutations. In contrast, PIG-A mutations in the CFCs from controls were polyclonal, and did not involve T cells. Our data confirm the finding that PIG-A mutations are relatively common in normal hematopoiesis; however, the finding suggests that these mutations occur in differentiated progenitors rather than HSCs.
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