ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

The anti-apoptotic transcription factor nuclear factor-κB (NF-κB) is constitutively activated in CD34⁺ myeloblasts from high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Inhibition of NF-κB by suppressing the canonical NF-κB activation pathway, for instance by knockdown of the three subunits of the inhibitor of NF-κB (IκB) 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-κB 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 IκBα and caused the relocalization of NF-κB 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-κB subunit, suggesting that an ATM inhibition/depletion truly induced apoptosis through inhibition of the NF-κB 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-κB in high-risk MDS and AML.