Involvement of Fas-mediated apoptosis in the inhibitory effects of
interferon-alpha in chronic myelogenous leukemia
C Selleri, T Sato, L Del Vecchio, L Luciano, AJ Barrett, B Rotoli, NS Young and JP Maciejewski
Hematology Division, Federico II University Medical School, Naples, Italy.
Interferon-alpha (IFN-alpha) is an established treatment for chronic
myelogenous leukemia (CML) in chronic phase, but the mechanism of its
antileukemic activity is not clear. One possible mechanism of action might
include the induction of apoptosis, and especially Fas-mediated cell
killing may play an important role in the elimination of malignant cells.
We investigated Fas receptor (Fas-R) expression and the consequences of
Fas-R triggering in CML patients. Using two-color flow cytometry, we found
a significantly higher number of Fas-R-expressing CD34+ cells in the bone
marrow (BM) of CML patients compared with normal subjects. We have
previously shown that IFN-gamma induces Fas-R expression on CD34+ cells; in
this study, we investigated whether IFN- alpha induces Fas-R expression on
CML progenitor cells. Dose-dependent induction of Fas-R expression was
observed after IFN-alpha stimulation of CD34+ cells from CML BM. In
methylcellulose culture, IFN-alpha alone at a therapeutic concentration
showed only marginal antiproliferative effects on both normal and CML BM
progenitors. In contrast, a Fas-R agonist, the anti-CD95 monoclonal
antibody CH11, inhibited colony formation from normal progenitors, and the
inhibition was even stronger on CML progenitors. When CML BM cells were
cultured in the presence of IFN-alpha, Fas-R-mediated inhibition of colony
growth was potentiated in a dose-dependent fashion, consistent with
IFN-alpha induction of Fas- R expression. This functional effect did not
require the presence of accessory cells, since similar results were
obtained with purified CD34+ cells. In suspension cultures, we demonstrated
that suppression of CML hematopoiesis by IFN-alpha and Fas-R agonist was
exerted through Fas-R-mediated induction of apoptosis. Our findings suggest
that the Fas-R/Fas-ligand system might be involved in the immunologic
regulation of CML progenitor growth and that its effect can be amplified by
IFN- alpha.
Volume 89,
Issue 3,
pp. 957-964,
02/01/1997
Copyright © 1997 by The American Society of Hematology
