叶酸多聚谷氨酸合成酶基因转录受一个多蛋白复合物调节，该复合物结合急性淋巴细胞白血病中的 TEL-AML1 融合蛋白。
Folylpolyglutamate synthetase gene transcription is regulated by a multiprotein complex that binds the TEL-AML1 fusion in acute lymphoblastic leukemia.
机构信息
Department of Pediatric Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
出版信息
Leuk Res. 2010 Dec;34(12):1601-9. doi: 10.1016/j.leukres.2010.05.012. Epub 2010 Jun 9.
Abstract
Acute Lymphoblastic Leukemia (ALL) non-random fusions influence clinical outcome and alter the accumulation of MTX-PGs in vivo. Analysis of primary ALL samples uncovered subtype-specific patterns of folate gene expression. Using an FPGS-luciferase reporter gene assay, we determined that E2A-PBX1 and TEL-AML1 expression decreased FPGS transcription. ChIP assays uncovered HDAC1, AML1, mSin3A, E2F, and Rb interactions with the FPGS promoter region. We demonstrate that FPGS expression is epigenetically regulated through binding of selected ALL fusions to a multiprotein complex, which also controls the cell cycle dependence of FPGS expression. This study provides insights into the pharmacogenomics of MTX in ALL subtypes.
摘要
急性淋巴细胞白血病（ALL）非随机融合影响临床结果，并改变体内 MTX-PGs 的积累。对原发性 ALL 样本的分析揭示了叶酸基因表达的亚型特异性模式。我们使用 FPGS-荧光素酶报告基因检测，确定 E2A-PBX1 和 TEL-AML1 的表达降低了 FPGS 转录。ChIP 检测揭示了 HDAC1、AML1、mSin3A、E2F 和 Rb 与 FPGS 启动子区域的相互作用。我们证明 FPGS 的表达是通过选择 ALL 融合与多蛋白复合物的结合来进行表观遗传调控的，该复合物还控制 FPGS 表达的细胞周期依赖性。这项研究为 ALL 亚型中甲氨蝶呤的药物基因组学提供了深入的了解。
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本文引用的文献
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mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia.雷帕霉素靶蛋白抑制剂与甲氨蝶呤具有协同作用：一种治疗急性淋巴细胞白血病的有效联合疗法。
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