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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 981-989
Fas-Mediated Modulation of Bcr/Abl in Chronic Myelogenous
Leukemia Results in Differential Effects on Apoptosis
Carmine Selleri,
Jaroslaw P. Maciejewski,
Fabrizio Pane,
Luigia Luciano,
Anna Maria Raiola,
Ilaria Mostarda,
Francesco Salvatore, and
Bruno Rotoli
From the Division of Hematology, CEINGE and Department of
Biochemistry and Biotechnology, Federico II University Medical School,
Naples, Italy; and the Department of Internal Medicine, University of
Nevada, Reno, NV.
Fas-R is expressed constitutively in CD34+ cells of
patients with chronic myelogenous leukemia (CML); Fas-R triggering
results in decreased proliferation rate due to apoptosis of clonogenic cells. We have already shown that  -interferon (IFN-) enhances Fas-R expression on CML progenitor cells, thus increasing their sensitivity to Fas-R agonists. Although it appears that IFN- can
prime CML cells for the effects of Fas, the response to IFN- in vivo
is not a constant feature in CML patients. We studied the mechanisms of
Fas-mediated apoptosis in 11 patients suffering from CML in chronic
phase and tried to see whether there was a correlation between in vitro
inducibility of apoptosis in CD34+ CML cells after Fas-R
triggering and the clinical response to IFN-. After priming with
IFN-, Fas triggering resulted in in vitro suppression of
hematopoietic cell growth in seven of eight patients who had optimal
hematologic response to IFN-; in the same conditions, no inhibitory
response to Fas-R agonist was observed in cells from three of three
patients who proved to be poor responders to IFN-. In responders to
IFN-, Fas-R agonist induced dose-dependent apoptosis of
CD34+ cells; this effect was associated with a decrease
in the bcr/abl protein level. In cells derived from patients
with a poor response to IFN-, the rate of apoptosis in culture
remained unchanged in the presence of Fas-R agonist and no
bcr/abl downmodulation was observed. Finally, we measured
bcr/abl mRNA by quantitative reverse-transcriptase polymerase
chain reaction (RT-PCR) and found that decreased bcr/abl
protein after Fas triggering was not associated with decreased amounts
of specific mRNA, a finding which is consistent with a
posttranscriptional regulation of the bcr/abl protein
expression. It appears that Fas-mediated downmodulation of p210
bcr/abl restores susceptibility to apoptosis of CML cells; in
addition, in vitro studies on CML cells may predict response to IFN-
treatment.
© 1998 by The American Society of Hematology.
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