Interleukin-1beta maintains an apoptosis-resistant phenotype in the blast cells of acute myeloid leukaemia via multiple pathways.
Blast cell survival in suspension culture is associated with chemoresistance in acute myeloid leukaemia (AML). Autonomous production of IL-1beta by AML blasts is linked with a proliferative response, although its role in survival and hence apoptosis-resistance has not been examined in this disease. Cells that secreted more than 19.7 pg/ml IL-1beta were significantly more resistant to spontaneous apoptosis in 48-h culture than those that produced less than 19.7 pg/ml IL-1beta (P=0.008). Exogenous rhIL-1beta significantly enhanced 48-h survival in 25/29 blast cell samples (P=0.0001). IL-1 receptor ligation is known to activate at least three survival pathways: those mediated by PI-3 kinase, IL-1 receptor-associated kinase (IRAK) and ceramidase. In apoptosis-sensitive AML blasts with a strong survival response to rhIL-1beta, inhibitors of all three pathways down-modulated an IL-1beta-mediated increase in blast survival, but only the inhibition of all three pathways totally eliminated viable blasts. In apoptosis-resistant and apoptosis-sensitive primary AML samples, the three inhibitors all increased apoptosis in vitro after 48 h. Exogenous rhIL-1beta induced the hyperphosphorylation of Bcl-2. It also increased the activation of NF-kappaB in 5/15 blast samples. IL-1beta-mediated survival pathways may be a factor in apoptosis-resistance in primary AML blasts, and may therefore contribute to chemoresistance.
Division of Haematology, University of Nottingham and Nottingham City Hospital, Nottingham, UK.
J
J
Turzanski
M
M
Grundy
N H
NH
Russell
M
M
Pallis
D000581:Amidohydrolases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D055572:Ceramidases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D000581:Amidohydrolases; D055572:Ceramidases