Journal
BLOOD
Volume 116, Issue 20, Pages 4240-4250Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-12-260711
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Funding
- Ligue Nationale Contre le Cancer (LNCC, comite de paris)
- Institut National du Cancer (INCa)
- Fondation de France
- Association Laurette Fugain
- Inserm
- Fondation pour la Recherche Medicale (FRM)
- Assistance Publique des Hopitaux de Paris/La Caisse Nationale d'Assurance Maladie (APHP/CANAM)
- Agence Nationale pour la Recherche
- Association pour la Recherche sur le Cancer
- Belgian InterUniversity
- Canceropole Ile-de-France
- Institut National du Cancer
- Universite Paris Descartes
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The FOXO transcription factors are involved in multiple signaling pathways and have tumor-suppressor functions. In acute myeloid leukemia (AML), deregulation of oncogenic kinases, including Akt, extra-signal-regulated kinase, or I kappa B kinase, is frequently observed, which may potentially inactivate FOXO activity. We therefore investigated the mechanism underlying the regulation of FOXO3a, the only FOXO protein constantly expressed in AML blast cells. We show that in both primary AML samples and in a MV4-11/FOXO3a-GFP cell line, FOXO3a is in a constant inactive state due to its cytoplasmic localization, and that neither PI3K/Akt nor extra-signal-regulated kinase-specific inhibition resulted in its nuclear translocation. In contrast, the anti-Nemo peptide that specifically inhibits IKK activity was found to induce FOXO3a nuclear localization in leukemic cells. Furthermore, an IKK-insensitive FOXO3a protein mutated at S-644 translocated into the nucleus and activated the transcription of the Fas-L and p21(Cip1) genes. This, in turn, inhibited leukemic cell proliferation and induced apoptosis. These results thus indicate that IKK activity maintains FOXO3a in the cytoplasm and establishes an important role of FOXO3a inactivation in the proliferation and survival of AML cells. The restoration of FOXO3a activity by interacting with its subcellular distribution may thus represent a new attractive therapeutic strategy for AML. (Blood. 2010;116(20):4240-4250)
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