Data from Epigenetic Control of NF-κB-Dependent <i>FAS</i> Gene Transcription during Progression of Myelodysplastic Syndromes

Abstract

<div>Abstract<p>The death domain containing TNF receptor 6 (CD95/Fas) is a direct target for the NF-κB transcription factor and is repressed in solid tumors such as colon carcinomas. Previously, we reported that the Fas death receptor, while overexpressed in low-risk myelodysplastic syndromes (MDS), becomes undetectable on CD34<sup>+</sup> progenitors when the disease progresses to secondary acute myeloid leukemia (AML). This study determined the interplay between NF-κB and Fas during MDS progression. We first observed that Fas was induced by TNF-α in the HL60 cell line. In these cells, p65 (RELA) was associated with the FAS promoter, and inhibition of the NF-κB pathway by an IKKα inhibitor (BAY11-7082) or lentiviral expression of a nondegradable mutant of IκBα (IκSR) blocked Fas expression. In contrast, TNF-α failed to induce Fas expression in the colon carcinoma cell line SW480, due to hypermethylation of the FAS promoter. Azacitidine rescued p65 binding on <i>FAS</i> promoter <i>in vitro</i>, and subsequently Fas expression in SW480 cells. Furthermore, inhibition of the NF-κB pathway decreased the expression of Fas in MDS CD45<sup>lo</sup>CD34<sup>+</sup> bone marrow cells. However, despite the nuclear expression of p65, Fas was often low on CD45<sup>lo</sup>CD34<sup>+</sup> AML cells. TNF-α failed to stimulate its expression, while azacitidine efficiently rescued p65 binding and Fas reexpression. Overall, these data suggest that DNA methylation at NF-κB sites is responsible for <i>FAS</i> gene silencing. <i>Mol Cancer Res; 11(7); 724–35. ©2013 AACR</i>.</p></div>