Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene

Abstract

With the use of ChIP on microarray assays in primary leukemia samples, we report that acute myeloid leukemia (AML) blasts exhibit significant alterations in histone H3 acetylation (H3Ac) levels at > 1000 genomic loci compared with CD34 ؉ progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared with 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 patients with AML. 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 on BM 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.

CBFB–MYH11/RUNX1 together with a compendium of hematopoietic regulators, chromatin modifiers and basal transcription factors occupies self-renewal genes in inv(16) acute myeloid leukemia

“…[32][33][34][35] Together these results suggest that genes important for maintaining leukemogenic potential (as evident from the targeting of CBFb-MYH11 to these regions) are regulated by many different transcription factors and coregulators and that most likely their interplay determines the transcriptional output.…”

“…[32][33][34][35] To examine whether both enzymatic activities are recruited to CBFb-MYH11 sites, we performed ChIP-seq using specific antibodies against HDAC1 and the HAT EP300. This analysis revealed the presence of both EP300 and HDAC1 at the CBFb-MYH11 sites at the HDAC1 and HM13 genes (Figure 4b).…”

NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

“…Increased ROS levels upon cytokine stimulation; low PRDX2 levels correlated with poor prognosis [29] A plethora of data has indicated alterations in ROS metabolism in leukemia, either linked to etiology, prognosis or therapy responses [30,31]. Many studies have supported the idea that ROS formation M A N U S C R I P T…”

Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species

“…A third possibility is altered epigenetic regulation of NRF2 itself. Epigenetic silencing of antioxidant genes, including the ARE-regulated PRDX2, has been previously reported in AML (39). Which, if any, of these explanations pertain to NPMc þ effects on the redox system remains to be explored.…”