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

Oncogene volume 28, pages 1099–1109 (2009)Cite this article

Abstract

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.

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Abbreviations

AML:

acute myeloid leukemia

BM-MNC:

bone marrow mononuclear cells

DAPI:

4′,6-diamidino-2-phenylindole

DiOC6(3):

3,3′ dihexyloxacarbocyanine iodide

IκB:

inhibitor of NF-κB

IKK:

IκB kinase

MDS:

myelodysplastic syndrome

NF-κB:

nuclear factor-κB

PI:

propidium iodide

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Acknowledgements

We are indebted to Jalil Abdelali (Institut Gustave Roussy, Villejuif, France) for technical support in confocal microscopy. Guido Kroemer is supported by the Agence Nationale de Recherche, Fondation de France, Cent pour Sang la Vie, Cancéropôle Ile-de-France, Institut National du Cancer, Ligue Nationale contre le Cancer and the European Community (Active p53, Apo-Sy, Apop-Train, TransDeath, RIGHT, ChemoRes). Jennifer Grosjean received a postdoctoral fellowship by Cancéropôle Ile-de-France. Lionel Adès received a scholarship from Assistance Publique-Hopitaux de Paris and Caisse Nationale d’Assurance Maladie des Professions Indépendantes. Claire Fabre received a scholarship from Fondation pour la Recherche Médicale. Maximilien Tailler received a PhD fellowship from Université Paris Sud, Paris 11.

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Authors and Affiliations

  1. INSERM U848, Institut Gustave Roussy, Villejuif, France

    J Grosjean-Raillard, M Tailler, L Adès, J-L Perfettini, C Fabre, P Fenaux & G Kroemer

  2. Institut Gustave Roussy, Villejuif, France

    J Grosjean-Raillard, M Tailler, L Adès, J-L Perfettini, C Fabre, S De Botton, P Fenaux & G Kroemer

  3. Université Paris Sud, Villejuif, France

    J Grosjean-Raillard, M Tailler, L Adès, J-L Perfettini, C Fabre, P Fenaux & G Kroemer

  4. Service d'Hématologie Clinique, Hôpital Avicenne, AP-HP, Université Paris XIII, Bobigny, France

    L Adès, T Braun & P Fenaux

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  1. J Grosjean-Raillard
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Correspondence to G Kroemer.

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JG-R and MT performed the experiments and analysed the data. LA, CF, TB and SDB provided BM samples and essential clinical information on patients. AI and PF participated in the conception of the study. GK conceived and directed the study. JG-R and GK wrote the paper.

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Grosjean-Raillard, J., Tailler, M., Adès, L. et al. ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia. Oncogene 28, 1099–1109 (2009). https://doi.org/10.1038/onc.2008.457

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