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- Title
Interleukin-1ßmaintains an apoptosis-resistant phenotype in the blast cells of acute myeloid leukaemia via multiple pathways.
- Authors
Turzanski, J.; Grundy, M.; Russell, N. H.; Pallis, M.
- Abstract
Blast cell survival in suspension culture is associated with chemoresistance in acute myeloid leukaemia (AML). Autonomous production of IL-1β 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 193 pg/ml IL-1β were significantly more resistant to spontaneous apoptosis in 48-h culture than those that produced less than 19.7 pg/ml IL-1β (P=0008). Exogenous rhIL-1β 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-1β, inhibitors of all three pathways down-modulated an IL-1β-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 48k Exogenous rhIL-β1 induced the hyperphosphorylation of Bcl-2. It also increased the activation of NF-κB in 5/15 blast samples. IL-1β-mediated survival pathways may be a factor in apoptosis-resistance in primary AML blasts, and may therefore contribute to chemoresistance.
- Subjects
ACUTE myeloid leukemia; MYELOID leukemia; LEUKEMIA; CELL death; APOPTOSIS; ANEMIA
- Publication
Leukemia (08876924), 2004, Vol 18, Issue 10, p1662
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/sj.leu.2403457