TY - JOUR
T1 - A novel effect of DNA methyltransferase and histone deacetylase inhibitors
T2 - NFκB inhibition in malignant myeloblasts
AU - Fabre, Claire
AU - Grosjean, Jennifer
AU - Tailler, Maximilien
AU - Boehrer, Simone
AU - Adès, Lionel
AU - Perfettini, Jean Luc
AU - De Botton, Stéphane
AU - Fenaux, Pierre
AU - Kroemer, Guido
PY - 2008/7/15
Y1 - 2008/7/15
N2 - 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 NFκB. We found that DNA methyltransferase (DNMT) inhibitors (such as azacytidine and 5-aza-′-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 NFκB (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 NFκB- activating kinase IKKα/β, 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 NFκB and IKKα/β. Altogether, these results indicate that DNMT and HDAC inhibitors can inhibit the constitutive activation of NFκB in malignant myeloblasts in vitro and in vivo through a novel mechanism.
AB - 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 NFκB. We found that DNA methyltransferase (DNMT) inhibitors (such as azacytidine and 5-aza-′-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 NFκB (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 NFκB- activating kinase IKKα/β, 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 NFκB and IKKα/β. Altogether, these results indicate that DNMT and HDAC inhibitors can inhibit the constitutive activation of NFκB in malignant myeloblasts in vitro and in vivo through a novel mechanism.
KW - Acute myeloid leukaemia
KW - DNA methyltransferase inhibitors
KW - Histone deacetylase inhibitors
KW - Myelodysplastic syndrome
UR - http://www.scopus.com/inward/record.url?scp=47749083495&partnerID=8YFLogxK
U2 - 10.4161/cc.7.14.6268
DO - 10.4161/cc.7.14.6268
M3 - Article
C2 - 18641459
AN - SCOPUS:47749083495
SN - 1538-4101
VL - 7
SP - 2139
EP - 2145
JO - Cell Cycle
JF - Cell Cycle
IS - 14
ER -