期刊
CELL CYCLE
卷 7, 期 14, 页码 2139-2145出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.7.14.6268
关键词
acute myeloid leukemia; DNA methyltransferase inhibitors; histone deacetylase inhibitors; myelodysplastic syndrome
类别
资金
- Fondation pour la Recherche Medicale
- Ministere de la Recherche
- Deutsche Forschungsgemeinschaft
- Assistance Publique-Hopitaux de Paris
- Caisse Nationale d'Assurance Maladie des Professions Independantes
- Institut National du Cancer
- Fondation de France
- Association Laurette Fugain
- Cent pour Sang la Vie
- Agence Nationale de la Recherche
- European Commission
Malignant myeloblasts arising in high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are characterized by the constitutive activation of the anti-apoptotic transcription factor NF kappa B. We found that DNA methyltransferase (DNMT) inhibitors (such as azacytidine and 5-aza-2'-deoxycytidine) and histone deacetylase (HDAC) inhibitors (such as trichostatin and valproic acid) efficiently induced apoptosis in the P39 MDS/AML cell line, correlating with an inhibition of NF kappa B (which translocated from the nucleus to the cytoplasm). This effect was obtained rapidly, within a few hours, suggesting that it was not due to epigenetic reprogramming. Indeed, DNMT and HDAC inhibitors reduced the phosphorylation of the NF kappa B-activating kinase IKK alpha/beta, and this effect was also observed in enucleated cells. Finally, circulating myeloblasts from AML patients treated with the DNMT inhibitor 5-aza-2'-deoxycytidine manifested a rapid (2 hours post-treatment) inhibition of NF kappa B and IKK alpha/beta. Altogether, these results indicate that DNMT and HDAC inhibitors can inhibit the constitutive activation of NF kappa B in malignant myeloblasts in vitro and in vivo through a novel mechanism.
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