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In the present study, we aimed to elucidate the mechanism responsible for constitutive NF-?B DNA-binding activity in AML cells. Intervening in aberrant signaling pathway provides a rational approach for in vivo targeting of AML cells. Constitutive NF-?B 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-?B activity by the NF-?B inhibitor SN-50 peptide resulted in enhanced chemotherapy-induced apoptosis. In the majority of cases, constitutive NF-?B 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-?B 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-?B 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, -TNFa or the tyrosine kinase inhibitor AG1296 did not affect the NF-?B DNA-binding activity. The present study demonstrates that Ras activation is an important pathway for triggering the NF-?B pathway in AML cells.Leukemia (2004) 18, 103-112. doi:10.1038/sj.leu.2403145 [ABSTRACT FROM AUTHOR]