Evidence for internal autocrine regulation of growth in acute myeloblastic leukemia cells.
Blast cells from 70% of patients with acute myeloid leukemia (AML) show some evidence of in vitro autonomous growth, which appears to be related to the autocrine secretion of growth factors, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF). In the majority of cases, the growth factors appear to be involved in classical extracellular autocrine or paracrine loops with neutralizing antibodies to the relevant cytokine inhibiting growth. In a minority, however, antibodies do not inhibit growth despite evidence of secretion of the cytokine. There is evidence for intracellular autocrine loops in murine leukemic cell lines. In this study, we wished to investigate for the presence of such intracellular loops involving GM-CSF in AML blast cells. Blast cells from 11 patients with AML were cultured in the presence of either neutralizing GM-CSF antibody or an antisense oligonucleotide directed against GM-CSF. We also studied the effect of the oligonucleotide on the autonomous growth of cells whose production of GM-CSF had been apparently abolished by either interleukin-1 receptor antagonist (IL-1Ra) or following blast cell purification using the CD34 antigen. The autonomous growth of the blast cells from nine of the 11 patients was inhibited by the antisense oligonucleotide (but not by the control sense oligonucleotide). However, only six of the nine were inhibited by the anti-GM-CSF antibody. Similarly, in one patient whose CD34 purified blast cells continued to show a high degree of autonomous growth but did not produce detectable GM-CSF, growth was inhibited by the antisense oligonucleotide but not by antibody, while in another patient whose cells were inhibited by IL-1Ra with, again, loss of detectable GM-CSF, growth could be further inhibited by the addition of the oligonucleotide but not the antibody. These studies provide evidence that intracellular autocrine loops involving GM-CSF are involved in the autonomous growth of some AML blast cells.
Rogers
S Y
SY
Department of Haematology, Nottingham City Hospital, UK.
Bradbury
D
D
Kozlowski
R
R
Russell
N H
NH
D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000906:Antibodies; D015703:Antigens, CD; D018952:Antigens, CD34; D007375:Interleukin-1; D016376:Oligonucleotides, Antisense; D016178:Granulocyte-Macrophage Colony-Stimulating Factor