Constitutive NF-κB DNA-binding activity in AML is frequently mediated by a Ras/PI3-K/PKB-dependent pathway

被引:119
作者
Birkenkamp, KU
Geugien, M
Schepers, H
Westra, J
Lemmink, HH
Vellenga, E
机构
[1] Univ Groningen, Dept Med, Div Hematol, NL-9700 AB Groningen, Netherlands
[2] Univ Groningen, Dept Med Genet, NL-9700 AB Groningen, Netherlands
关键词
myeloid leukemia; Ras; NF-kappa B; PI3-K; PKB;
D O I
10.1038/sj.leu.2403145
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
In the present study, we aimed to elucidate the mechanism responsible for constitutive NF-kappaB DNA-binding activity in AML cells. Intervening in aberrant signaling pathway provides a rational approach for in vivo targeting of AML cells. Constitutive NF-kappaB DNA-binding activity was observed in 16 of 22 (73%) investigated AML cases and was, in general, associated with resistance to spontaneous apoptosis. Indeed, inhibition of NF-kappaB activity by the NF-kappaB inhibitor SN-50 peptide resulted in enhanced chemotherapy-induced apoptosis. In the majority of cases, constitutive NF-kappaB activity was mediated by a Ras/PI3 kinase (PI3-K)/protein kinase B (PKB)-mediated pathway. The PI3-K inhibitor Ly294002 and the Ras inhibitor L-744832 both inhibited PKB phosphorylation and NF-kappaB DNA-binding activity. The constitutive activation of Ras GTP-ase was caused by mutations in the gene encoding for N-Ras in 29% of the cases. The constitutive NF-kappaB activity could so far not be ascribed to the autocrine production of growth factors or to mutations in the Flt3 receptor, since anti-GM-CSF, -IL-1, -IL6, -TNFalpha or the tyrosine kinase inhibitor AG1296 did not affect the NF-kappaB DNA-binding activity. The present study demonstrates that Ras activation is an important pathway for triggering the NF-kappaB pathway in AML cells.
引用
收藏
页码:103 / 112
页数:10
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