the antioxidant protein peroxiredoxin 4 is epigenetically down regulated in acute promyelocytic leukemia抗氧化蛋白酶类4是epigenetically调节急性早幼粒细胞白血病.pdfVIP

The Antioxidant Protein Peroxiredoxin 4 Is Epigenetically Down Regulated in Acute Promyelocytic Leukemia 1 1 1 2 1 Karishma K. Palande , Renee Beekman , Lotte E. van der Meeren , H. Berna Beverloo , Peter J. M. Valk , Ivo P. Touw1* 1 Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands, 2 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands Abstract The antioxidant peroxiredoxin (PRDX) protein family comprises 6 members, which are implicated in a variety of cellular responses, including growth factor signal transduction. PRDX4 resides in the endoplasmic reticulum (ER), where it locally controls oxidative stress by reducing H2O2 levels. We recently provided evidence for a regulatory function of PRDX4 in signal transduction from a myeloid growth factor receptor, the granulocyte colony-stimulating factor receptor (G-CSFR). Upon activation, the ligand-induced G-CSFR undergoes endocytosis and routes via the early endosomes where it physically interacts with ER-resident PRDX4. PRDX4 negatively regulates G-CSFR mediated signaling. Here, we investigated whether PRDX4 is affected in acute myeloid leukemia (AML); genomic alterations and expression levels of PRDX4 were investigated. We show that genomic abnormalities involving PRDX4 are rare in AML. However, we find a strong reduction in PRDX4 expression levels in acute promyelocytic leukemia (APL) compared to normal promyelocytes and different molecular subtypes of AML. Subsequently, the possible role of DNA methylation and histone modifications in silencing of PRDX4 in APLs was investigated. We show that the reduced expression is not due to