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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-09-2898.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2591-2600
HEMATOPOIESIS
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
From the Department of Hematology of the University of
Crete School of Medicine and Institute of Molecular Biology and
Biotechnology, Heraklion, Crete, Greece; Cancer Research
United Kingdom Institute for Cancer Studies of the University of
Birmingham Medical School, United Kingdom; and Institute
of Clinical Immunology and Transfusion Medicine of the Justus-Liebig
University, Giessen, Germany.
To probe the pathophysiologic mechanisms 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 adults with CIN 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 patients with CIN displayed a 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 (LTBMCs), compared with controls (n = 46). A low
percentage of CD34+/CD33+ cells in patients was
associated with accelerated apoptosis and Fas overexpression within
this cell compartment compared with controls. No significant difference
was documented in the percentage of apoptotic cells or the
Fas+ cells within the fractionated
CD34+/CD33 ,
CD34/CD33+, and
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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