title: ATM mediates constitutive NF-kappaB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia.
abstract: 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.
authors.affiliation: INSERM U848, Institut Gustave Roussy, Villejuif, France.
authors.forename: J
authors.initials: J
authors.lastname: Grosjean-Raillard
authors.forename: M
authors.initials: M
authors.lastname: Tailler
authors.forename: L
authors.initials: L
authors.lastname: Adès
authors.forename: J-L
authors.initials: JL
authors.lastname: Perfettini
authors.forename: C
authors.initials: C
authors.lastname: Fabre
authors.forename: T
authors.initials: T
authors.lastname: Braun
authors.forename: S
authors.initials: S
authors.lastname: De Botton
authors.forename: P
authors.initials: P
authors.lastname: Fenaux
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D021581:Active Transport, Cell Nucleus; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology*; D064007:Ataxia Telangiectasia Mutated Proteins; D001854:Bone Marrow Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053418:Death Domain Receptor Signaling Adaptor Proteins; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D012307:Risk Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; C491731:IKBKG protein, human; D016328:NF-kappa B; C485896:PIDD1 protein, human; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase