LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro.
LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro.
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LEDGF/p75的表达增加了抗化疗的人类急性髓性白血病患者的爆炸表达，并保护白血病细胞不受体外凋亡。
DOI：
10.1186/1476-4598-6-31
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发表时间：
2007-04-23
期刊：
影响因子：
37.3
通讯作者：
Lillehaug, Johan R
中科院分区：
文献类型：
--
作者：
Huang, Tien-sheng;Myklebust, Line M;Kjarland, Endre;Gjertsen, Bjorn Tore;Pendino, Frederic;Bruserud, Oystein;Doskeland, Stein Ove;Lillehaug, Johan R
耐药残留病导致的复发是急性髓性白血病（AML）死亡的主要原因。本研究通过比较耐药复发AML和化疗敏感AML患者原始细胞中差异基因表达来阐明化疗耐药的分子机制。基于差异基因表达筛选，与化学敏感性AML原始细胞相比，约20个基因被鉴定为在合并自耐药疾病患者的原始细胞中优先表达。这些基因中有一半编码与蛋白质翻译相关的蛋白质，其中一种与核糖体柄蛋白P0相关的新蛋白质。其他上调的mRNA编码细胞色素C氧化酶III、转录因子ERF-2/TIS 11 d以及透镜上皮衍生生长因子（LEDGF）的p75和p52剪接变体。单个患者的原始细胞分析显示，LEDGF/p75是耐药AML中最一致上调的mRNA。转染实验表明，LEDGF/p75和p52 b拮抗柔红霉素诱导和cAMP诱导的AML细胞系的凋亡。LEDGF/p75和p52 b也可保护HEK-293细胞免受柔红霉素的侵害，而LEDGF/p52剪接变体缺失外显子6具有促凋亡作用。有趣的是，全长LEDGF/p75保护免受截短的促凋亡LEDGF/p75。我们的研究结果为编码生存蛋白（如LEDGF/p75）的基因过表达与急性髓细胞白血病化疗耐药性之间的关联提供了证据。LEDGF/p75以前没有显示出对化疗的保护作用，并且是AML中的潜在药物靶点。
Relapse due to chemoresistant residual disease is a major cause of death in acute myelogenous leukemia (AML). The present study was undertaken to elucidate the molecular mechanisms of chemoresistance by comparing differential gene expression in blasts from patients with resistant relapsing AML and chemosensitive AML. About 20 genes were identified as preferentially expressed in blasts pooled from patients with resistant disease, as compared to chemosensitive AML blasts, based on differential gene expression screening. Half of these genes encoded proteins related to protein translation, of these a novel protein related to the ribosomal stalk protein P0. Other upregulated mRNAs coded for cytochrome C oxidase III, the transcription factors ERF-2/TIS11d, and the p75 and p52 splice variants of Lens Epithelial Derived Growth Factor (LEDGF). Analysis of blasts from single patients disclosed that LEDGF/p75 was the most consistently upregulated mRNA in resistant AML. Transfection experiments demonstrated that LEDGF/p75 and p52b antagonized daunorubicin-induced and cAMP-induced apoptosis in an AML cell line. Also HEK-293 cells were protected against daunorubicin by LEDGF/p75 and p52b, whereas LEDGF/p52 splice variants lacking exon 6 had proapoptotic effects. Interestingly, full length LEDGF/p75 protected against truncated pro-apoptotic LEDGF/p75. Our results provide evidence for an association between the overexpression of genes encoding survival proteins like LEDGF/p75 and chemo-resistance in acute myelogenous leukemia. LEDGF/p75 has previously not been shown to protect against chemotherapy, and is a potential drug target in AML.