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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-09-2898.
Submitted September 23, 2002
Accepted November 18, 2002
Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells
Helen A Papadaki*, Aristides G Eliopoulos, Theodoros Kosteas, Claudia Gemetzi, Athina Damianaki, Helen Koutala, Juergen Bux, and George D Eliopoulos
Hematology, University of Crete School of Medicine, Heraklion, Crete, Greece
Cancer Research UK Institute for Cancer Studies of the University of Birmingham Medical School, Birmingham, United Kingdom
Institute of Molecular Biology and Biotechnology, Heraklion, Crete, Greece
Institute of Clinical Immunology and Transfusion Medicine of the Justus-Liebig University, Giessen, Germany
* Corresponding author; email: epapadak{at}med.uoc.gr.
To probe the pathophysiologic mechanism(s) underlying neutropenia in patients with chronic idiopathic neutropenia (CIN) with hypoplastic and left shifted granulocytic series in the bone marrow (BM), we have studied granulocytopoiesis in 32 CIN adults by evaluating the number and survival characteristics of cells in several stages of granulocyte differentiation using flow-cytometry and BM culture assays. We found that CIN patients displayed low percentage of CD34+/CD33+ cells, defective granulocyte colony-forming unit (CFU-G) growth potential of BM mononuclear or purified CD34+ cells and low CFU-G recovery in long-term BM cultures (LTBMC), compared to controls (n=46). Low percentage of CD34+/CD33+ cells in patients was associated with accelerated apoptosis and Fas over-expression within this cell compartment, compared to controls. No significant difference was documented in the percentage of apoptotic cells or the Fas+ cells within the fractionated CD34+/CD33-, CD34-/CD33+, CD34-/CD33-/CD15+ BM subpopulations or the peripheral blood neutrophils, suggesting that the underlying cellular defect in CIN probably concerns the committed granulocyte progenitors. LTBMC stromal layers from patients produced abnormally high amounts of tumor necrosis factor- and cytokine levels in culture supernatants inversely correlated with the number of myeloid progenitor cells and positively with the proportion of apoptotic CD34+ cells. Patient LTBMC stromal layers displayed pathologic interferon- and Fas-Ligand mRNA expression and failed to support normal myelopoiesis. These data suggest that impaired granulocytopoiesis in CIN is probably due to overproduction of inflammatory cytokines by immune cells within the BM microenvironment that may exert an inhibitory effect on myelopoiesis by inducing Fas-mediated apoptosis in the granulocyte progenitors.
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