Blood, 15 December 2000, Vol. 96, No. 13, pp. 4118-4123
HEMATOPOIESIS
Evidence that ceramide mediates the ability of tumor necrosis
factor to modulate primitive human hematopoietic cell fates
Veronique Maguer-Satta,
Robert Oostendorp,
Dianne Reid, and
Connie J. Eaves
From the Terry Fox Laboratory, British Columbia Cancer
Agency, Vancouver, BC, Canada.
In this study, it is shown that short-term exposure of normal human
marrow CD34+CD38
cells to low concentrations
of tumor necrosis factor (TNF) in the presence of 100 ng/mL Flt3 ligand
and Steel factor and 20 ng/mL interleukin-3 (IL-3), IL-6, and
granulocyte colony-stimulating factor, in either bulk or single-cell
serum-free cultures, markedly reduces their ability subsequently to
generate colony-forming cells (CFCs) in 6-week stromal cell-containing
long-term cultures without affecting their viability, mitogenic
response, or short-term ability to produce CFCs. A similar differential
effect on the functional attributes of
CD34+CD38 cells was seen when C2- or
C6-ceramide, but not dihydro-C2-ceramide (an inactive analog of
ceramide), was substituted for TNF. The addition of D-erythro-MAPP (a
specific inhibitor of intracellular ceramide degradation) enhanced the
ability of TNF to selectively eliminate long-term culture-initiating
cell (LTC-IC) activity. These findings indicate that TNF can directly
modulate the ability of CD34+CD38 cells to
maintain their LTC-IC function at doses below those required to
initiate apoptosis, cell cycle arrest, or both, and they suggest that
this may be mediated by the TNF-induced generation of intracellular
ceramide. Identification of a signaling intermediate that can influence
primitive hematopoietic cell fate decisions offers a new approach to
the investigation of signaling mechanisms in normal stem cell
populations and to how these may be altered in leukemic cells.
