Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
PLoS One. 2011 Jan 20;6(1):e16340. doi: 10.1371/journal.pone.0016340.
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 H(2)O(2) 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 methylation of the CpG island in the promoter region of PRDX4 but correlates with increased trimethylation of histone 3 lysine residue 27 (H3K27me3) and lysine residue 4 (H3K4me3) at the transcriptional start site (TSS) of PRDX4, indicative of a bivalent histone code involved in transcriptional silencing. These findings suggest that the control of G-CSF responses by the antioxidant protein PRDX4 may be perturbed in APL.
抗氧化剂过氧化物酶 (PRDX) 蛋白家族由 6 个成员组成，它们参与多种细胞反应，包括生长因子信号转导。PRDX4 位于内质网 (ER) 中，在那里通过降低 H(2)O(2)水平来局部控制氧化应激。我们最近提供了证据表明 PRDX4 在髓样生长因子受体，即粒细胞集落刺激因子受体 (G-CSFR) 的信号转导中具有调节功能。配体诱导的 G-CSFR 激活后会发生内吞作用，并通过早期内体途径，在那里它与内质网驻留的 PRDX4 发生物理相互作用。PRDX4 负调节 G-CSFR 介导的信号转导。在这里，我们研究了 PRDX4 是否在急性髓细胞白血病 (AML) 中受到影响；研究了 PRDX4 的基因组改变和表达水平。我们表明，AML 中涉及 PRDX4 的基因组异常很少见。然而，我们发现与正常早幼粒细胞和不同的 AML 分子亚型相比，急性早幼粒细胞白血病 (APL) 中 PRDX4 的表达水平显著降低。随后，研究了 DNA 甲基化和组蛋白修饰在 APLs 中沉默 PRDX4 的可能作用。我们表明，表达的降低不是由于 PRDX4 启动子区域的 CpG 岛甲基化所致，而是与 PRDX4 转录起始位点 (TSS) 处组蛋白 3 赖氨酸残基 27 (H3K27me3) 和赖氨酸残基 4 (H3K4me3) 的三甲基化增加相关，表明涉及转录沉默的双价组蛋白密码。这些发现表明，抗氧化蛋白 PRDX4 对 G-CSF 反应的控制可能在 APL 中受到干扰。
