Genome wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene
Menée sur des échantillons tumoraux de leucémie myléoïde aiguë et à l'aide de xénogreffes, cette étude suggère que le gène PRDX2 est un suppresseur de tumeurs réduit au silence par un mécanisme épigénétique
Using ChIP-Chip assays in primary leukemia samples, we demonstrate that acute myeloid leukemia (AML) blasts exhibit significant alterations in Histone H3 acetylation (H3Ac) levels at more than 1000 genomic loci compared to CD34+ progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared to progenitor cells, which suggested that a large number of genes are epigenetically silenced in AML. Intriguingly, we identified Peroxiredoxin 2 (PRDX2) as a novel potential tumor suppressor gene in AML. H3Ac was decreased at the PRDX2 gene promoter in AML which correlated with low mRNA and protein expression. We also observed DNA hypermethylation at the PRDX2 promoter in AML. Low protein expression of the antioxidant PRDX2 gene was clinically associated with poor prognosis in AML patients. Functionally, PRDX2 acted as inhibitor of myeloid cell growth by reducing levels of reactive oxygen species (ROS) generated in response to cytokines. Forced PRDX2 expression inhibited c-Myc-induced leukemogenesis in vivo upon bone marrow transplantation in mice. Taken together, epigenome-wide analyses of H3Ac in AML, led to the identification of PRDX2 as an epigenetically silenced growth suppressor suggesting a possible role of ROS in the malignant phenotype in AML.