Deguelin induced differentiation of mutated NPM1 acute myeloid leukemia in vivo and in vitro
Deguelin induced differentiation of mutated NPM1 acute myeloid leukemia in vivo and in vitro
复制标题
Deguelin 体内外诱导突变 NPM1 急性髓系白血病的分化
DOI：
10.1097/cad.0000000000000494
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发表时间：
2017
影响因子：
2.3
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Zhang Xia;Zhao Zichu;Yi Sha;Wen Lu;He Jing;Hu Jingyu;Ruan Jun;Fang Jun;Chen Yan;Fang J;Chen Y
核磷蛋白(NPM1)是一种限制性核仁定位蛋白，穿梭于细胞核和细胞质之间。突变的(MT)-NPM1蛋白具有异常的核磷蛋白胞浆错位，约三分之一的急性髓系白血病患者会发生这种蛋白突变。鱼藤素是一种从几种植物中分离出来的鱼藤素，是一种强大的抗肿瘤药物。以人mt-NPM1 OCI/AML3细胞系异种移植NOD/SCID小鼠作为体内模型。Wright-Giemsa染色和流式细胞术分析细胞分化程度。通过蛋白质印迹和组织学分析评估相关的分子事件。Kaplan-Meier估计用于计算存活率。用免疫组织化学染色和血清标志物评价鱼藤素对小鼠的毒性。临床标本通过流式细胞仪分析进行鉴别。Dguelin通过下调mt-NPM1蛋白水平诱导分化，伴随着SIRT1、p21和HDAC1蛋白表达下降，CEBP和BGR蛋白表达增加，粒细胞集落刺激因子受体蛋白表达增加。与对照组相比，低剂量的鱼腥草素延长了小鼠的存活时间，并且在体内对脑、肝、心脏和肾脏没有明显的损害。在临床标本中，鱼腥草素可用mt-NPM1蛋白诱导新鲜母细胞分化，但不能用野生型NPM1蛋白诱导分化。综上所述，这些发现进一步为mt-NPM1蛋白在体内和体外诱导分化中发挥重要作用提供了新的证据。突变的NPM1蛋白可能是鱼藤素治疗NPM1突变的急性髓系白血病的靶点。
Nucleophosmin (NPM1), a restricted nucleolar localization protein, shuttles between the nucleus and the cytoplasm. Mutated (Mt)-NPM1 protein, which has aberrant cytoplasmic dislocation of nucleophosmin, occurs in approximately one-third of acute myeloid leukemia cases. Deguelin, a rotenoid isolated from several plant species, is a strong antitumor agent. NOD/SCID mice xenografted with human Mt-NPM1 OCI/AML3 cell lines served as in-vivo models. Wright–Giemsa staining and flow cytometry analysis were used for differentiation assays. Associated molecular events were assessed by western blot and histological analyses. Kaplan–Meier estimates were used to calculate survival. Deguelin toxicity in mice was assessed by immunohistochemistry staining and serum markers. Clinical samples were differentiated by flow cytometry analysis. Deguelin induced differentiation by downregulating the Mt-NPM1 protein levels, which was accompanied by a decrease in SIRT1, p21, and HDAC1 and an increase in CEBP&bgr; and granulocyte colony-stimulating factor receptor protein expression levels. A low-deguelin dose prolonged survival compared with the control group, and there were no apparent lesions to the brain, liver, heart, and kidney in vivo. In clinical samples, deguelin induced the differentiation of fresh blasts with Mt-NPM1 protein, but not with the wild-type NPM1 protein. Taken together, these findings further provide new evidence that the Mt-NPM1 protein plays an important role in inducing differentiation in vivo and in vitro. Mutated NPM1 protein may be a therapeutic target of deguelin in acute myeloid leukemia with the NPM1 mutation.