Abstract

Epigenetic silencing of tumor suppressors is a frequent event in leukemogenesis. We performed ChIP-Chip to identify genes with altered Histone H3 acetylation in primary AML specimens (n=115) and normal CD34+ progenitor cells (n=21). Interestingly, promoters of several members of the peroxiredoxin family (PrdxII and Prdx IV) were identified to be significantly Histone H3 hypoacetylated in primary AML blasts. Peroxiredoxins (Prdx) are antioxidant enzymes that regulate the amount of reactive oxygen species in the cell. Prdx scavenge H2O2 and protect cells from oxidative damage to cellular DNA, lipid and proteins. Confirmation by quantitative PCR revealed that the PrdxII promoter was hypoacetylated in AML, and mRNA expression was 10-fold induced in U937 cells upon exposure to the demethylating agent 5-Azadeoxycytidine (Aza). Demethylation of U937 cells by Aza resulted in increased Histone H3 acetylation at the PrdxII promoter. DNA hypermethylation was frequent in primary AML blasts (18/103) but not in control samples (0/40) as assessed by methylation-specific PCR. Hypoacetylation of Histone H3 and DNA hypermethylation was associated with repression of PrdxII mRNA and protein levels in primary AML samples. Decreased PrdxII protein expression as assessed by immunohistochemistry in a tissue microarray was associated with a poor prognosis in AML patients. On the functional level, PrdxII inhibited the growth of hematopoietic progenitor cells in colony assays and negatively influenced receptor tyrosine kinase signaling by inhibition of ERK and AKT activation upon overexpression. Conversely, PrdxII knock-down by shRNA in myeloid progenitor cell lines and in murine primary bone marrow cells led to enhanced growth and tyrosine kinase signaling. A decrease in PrdxII levels was associated with an increase in reactive oxygen species and enhanced phosphorylation of STAT5, AKT and ERK. Taken together, these findings suggest that chromatin modifications in AML suppress expression of PrdxII. Our data also revealed that PrdxII is a novel putative tumor suppressor in AML.

Disclosures: No relevant conflicts of interest to declare.

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