Fas-mediated modulation of Bcr/Abl in chronic myelogenous leukemia results in differential effects on apoptosis.
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 alpha-interferon (IFN-alpha) enhances Fas-R expression on CML progenitor cells, thus increasing their sensitivity to Fas-R agonists. Although it appears that IFN-alpha can prime CML cells for the effects of Fas, the response to IFN-alpha 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-alpha. After priming with IFN-alpha, Fas triggering resulted in in vitro suppression of hematopoietic cell growth in seven of eight patients who had optimal hematologic response to IFN-alpha; 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-alpha. In responders to IFN-alpha, 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-alpha, 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-alpha treatment.
Selleri
C
C
Division of Hematology, CEINGE and Department of Biochemistry and Biotechnology, Federico II University Medical School, Naples, Italy.
Maciejewski
J P
JP
Pane
F
F
Luciano
L
L
Raiola
A M
AM
Mostarda
I
I
Salvatore
F
F
Rotoli
B
B
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology* / Q000628:therapy; D015466:Leukemia, Myeloid, Chronic-Phase / Q000473:pathology* / Q000628:therapy; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019014:fas Receptor; D016044:Fusion Proteins, bcr-abl