Increased IκB kinase activity is associated with activated NF-κB in acute myeloid blasts

被引:74
作者
Baumgartner, B
Weber, M
Quirling, M
Fischer, C
Page, S
Adam, M
von Schilling, C
Waterhouse, C
Schmid, C
Neumeier, D
Brand, K
机构
[1] Tech Univ Munich, Klinikum Rechts Isar, Inst Clin Chem & Pathobiol, D-81675 Munich, Germany
[2] Tech Univ Munich, Klinikum Rechts Isar, Dept Hematol Oncol, D-81675 Munich, Germany
[3] Univ Munich, Inst Clin Chem, Klinikum Grosshadern, D-80539 Munich, Germany
[4] Univ Munich, Dept Hematol Oncol, Klinikum Grosshadern, D-80539 Munich, Germany
[5] Akad Lehrkrankenhaus Munchen, Dept Hematol Oncol, Schwabing, Germany
关键词
AML; NF-kappa B; IKK complex; leukemia;
D O I
10.1038/sj.leu.2402641
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
NF-kappaB/Rel transcription factors are modulators of immune and inflammatory processes and are also involved in malignancy. Phosphorylation of the IkappaB inhibitors by the IkappaB kinase (IKK) complex leads to their proteasomal degradation, resulting in activated NF-kappaB. Here, we investigated the activation status of NF-kappaB and the IKK complex in acute myeloid leukemia (AML). Gelshift assays revealed an increased level of activated nuclear NF-kappaB in myeloid blasts. Both bone marrow and peripheral blood blasts from AML patients showed enhanced IKK activity relative to controls, whereas the IKK protein concentrations were comparable. In addition, an increased level of IkappaB-alpha was detected in AML blast cells, although this appeared to be insufficient to block nuclear translocation of NF-kappaB, also confirmed by immunofluorescence. In subtype M4 and M5 AML cells a more extensive NF-kappaB activation and higher IKK activity was found than in M1/M2 specimens. Isolated AML blasts cultured ex vivo responded to external stimulation (TNF, LPS) by further IKK activation, IkappaB degradation and NF-kappaB activation. Preincubation with the proteasome inhibitor PSI inhibited the NF-kappaB system in isolated AML blasts. This study established for the first time a dysregulation of IKK signaling in AML leading to increased NF-kappaB activity suggesting potential therapeutic avenues.
引用
收藏
页码:2062 / 2071
页数:10
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