Regulation of Bcl-2 expression and apoptosis in acute myeloblastic leukaemia cells by granulocyte-macrophage colony-stimulating factor.
Previous studies have shown that the bcl-2 gene encodes a mitochondrial protein which can inhibit the onset of apoptosis induced by withdrawal of trophic factors or by antitumour drugs. In some malignant cells bcl-2 expression has been demonstrated to be regulated by specific trophic factors which act to suppress apoptosis. Here we have investigated the effect of exogenous and autocrine granulocyte-macrophage colony-stimulating factor (GM-CSF) on both bcl-2 expression and apoptosis in acute myeloid leukaemia (AML) cells. Blasts from 31 patients with AML were studied, this included 21 patients whose cells exhibited variable degrees of autonomous growth in culture and ten patients with non-autonomous growth. Blasts with autonomous growth expressed significantly higher levels of bcl-2 protein, the intensity of fluorescence expressed as soluble fluorochrome per cell was 40.9 +/- 3.6 x 10(3) (mean +/- SD); this compared with an intensity of bcl-2 expression of 19.3 +/- 2.4 x 10(3) for blasts with non-autocrine growth (p < 0.0001 by Mann-Whitney analysis). Blasts with non-autocrine growth rapidly lost viability following 48 h of culture due to the onset of apoptosis. In these cells apoptosis was suppressed by the addition of GM-CSF and bcl-2 protein expression was found to be significantly upregulated. In contrast blasts from patients with autonomous growth and autocrine GM-CSF production failed to show any features of apoptosis in culture. In these cells bcl-2 expression was significantly downregulated following neutralization of autocrine GM-CSF by antibodies. We conclude that bcl-2 expression in AML cells is regulated by GM-CSF, and suggest that the previously demonstrated negative prognostic effect of autocrine growth as a determinant of treatment outcome in AML is in part due to the effect of autocrine GM-CSF in upregulating bcl-2 expression.
Bradbury
D
D
Department of Haematology, Nottingham City Hospital, UK.
Zhu
Y M
YM
Russell
N
N
D017209:Apoptosis / Q000235:genetics*; D002455:Cell Division; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor