The anti-apoptotic transcription factor nuclear factor-kappaB (NF-kappaB) is 
constitutively activated in CD34(+) myeloblasts from high-risk myelodysplastic 
syndrome (MDS) and acute myeloid leukemia (AML) patients. Inhibition of 
NF-kappaB by suppressing the canonical NF-kappaB activation pathway, for 
instance by knockdown of the three subunits of the inhibitor of NF-kappaB (I 
kappaB) kinase (IKK) complex (IKK1, IKK2 and NEMO) triggers apoptosis in such 
cells. Here, we show that an MDS/AML model cell line exhibits a constitutive 
interaction, within the nucleus, of activated, S1981-phosphorylated ataxia 
telangiectasia mutated (ATM) with NEMO. Inhibition of ATM with two distinct 
pharmacological inhibitors suppressed the activating autophosphorylation of ATM, 
blocked the interaction of ATM and NEMO, delocalized NEMO as well as another 
putative NF-kappaB activator, PIDD, from the nucleus, abolished the activating 
phosphorylation of the catalytic proteins of the IKK complex (IKK1/2 on serines 
176/180), enhanced the expression of I kappaB alpha and caused the 
relocalization of NF-kappaB from the nucleus to the cytoplasm, followed by 
apoptosis. Knockdown of ATM with small-interfering RNAs had a similar effect 
that could not be enhanced by knockdown of NEMO, PIDD and the p65 NF-kappaB 
subunit, suggesting that an ATM inhibition/depletion truly induced apoptosis 
through inhibition of the NF-kappaB system. Pharmacological inhibition of ATM 
also induced the nucleocytoplasmic relocalization of p65 in malignant 
myeloblasts purified from patients with high-risk MDS or AML, correlating with 
the induction of apoptosis. Altogether, these results support the contention 
that constitutively active ATM accounts for the activation of NF-kappaB in 
high-risk MDS and AML.