Involvement of Fas-Mediated Apoptosis in the Inhibitory Effects of Interferon-α in Chronic Myelogenous Leukemia

Author:

Selleri Carmine1,Sato Tadatsugu1,Del Vecchio Luigi1,Luciano Luigia1,Barrett A. John1,Rotoli Bruno1,Young Neal S.1,Maciejewski Jaroslaw P.1

Affiliation:

1. From the Hematology Division, Federico II University Medical School, Naples; the Immunohematology Service, Cardarelli Hospital, Naples, Italy; and the Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD.

Abstract

AbstractInterferon-α (IFN-α) 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-γ induces Fas-R expression on CD34+ cells; in this study, we investigated whether IFN-α induces Fas-R expression on CML progenitor cells. Dose-dependent induction of Fas-R expression was observed after IFN-α stimulation of CD34+ cells from CML BM. In methylcellulose culture, IFN-α 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-α, Fas-R–mediated inhibition of colony growth was potentiated in a dose-dependent fashion, consistent with IFN-α 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-α 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-α.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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