Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells
- 1 April 2003
- journal article
- Published by American Society of Hematology in Blood
- Vol. 101 (7) , 2591-2600
- https://doi.org/10.1182/blood-2002-09-2898
Abstract
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 α 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 γ 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.Keywords
This publication has 36 references indexed in Scilit:
- Stem cell defect in aplastic anemia: reduced long term culture-initiating cells (LTC-IC) in CD34+ cells isolated from aplastic anemia patient bone marrowThe Hematology Journal, 2002
- Acute and chronic neutropenias. What is new?Journal of Internal Medicine, 2001
- Assessment of bone marrow stem cell reserve and function and stromal cell function in patients with severe congenital neutropeniaEuropean Journal of Haematology, 2001
- Low frequency of myeloid progenitor cells in chronic idiopathic neutropenia of adults may be related to increased production of TGF‐β1 by bone marrow stromal cellsEuropean Journal of Haematology, 1999
- Interferon‐γ and tumor necrosis factor‐α suppress both early and late stages of hematopoiesis and induce programmed cell deathJournal of Cellular Physiology, 1995
- Requirement of P56lck in T-Cell Receptor CD3-Mediated Apoptosis and Fas-Ligand Induction Jurkat CellsBiochemical and Biophysical Research Communications, 1995
- Clinical Relevance of in Vitro Study of GranulocytopoiesisScandinavian Journal of Haematology, 1981
- Natural History of Chronic Idiopathic NeutropeniaNew England Journal of Medicine, 1980
- Chronic NeutropeniaMedicine, 1979
- Leukokinetic StudiesJournal of Clinical Investigation, 1971