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, Bruno Rotoli

Research output: Contribution to journalArticle

Abstract

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 α-interferon (IFN-α) enhances Fas-R expression on CML progenitor cells, thus increasing their sensitivity to Fas-R agonists. Although it appears that IFN-α can prime CML cells for the effects of Fas, the response to IFN-α 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-α. After priming with IFN-α, Fas triggering resulted in in vitro suppression of hematopoietic cell growth in seven of eight patients who had optimal hematologic response to IFN-α; 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- α. In responders to IFN-α, 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- α, the rate of apoptosis in culture remained unchanged in the presence of Fas-R agonist and no bcr/abl down-modulation 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 down-modulation of p210 bcr/abl restores susceptibility to apoptosis of CML cells; in addition, in vitro studies on CML cells may predict response to IFN-α treatment.

Original languageEnglish
Pages (from-to)981-989
Number of pages9
JournalBlood
Volume92
Issue number3
Publication statusPublished - Aug 1 1998

ASJC Scopus subject areas

  • Hematology

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    Selleri, C., Maciejewski, J. P., Pane, F., Luciano, L., Raiola, A. M., Mostarda, I., Salvatore, F., & Rotoli, B. (1998). Fas-mediated modulation of Bcr/Abl in chronic myelogenous leukemia results in differential effects on apoptosis. Blood, 92(3), 981-989.